Well, we certainly have a terrific turnout this afternoon. I think the reason for it was because you all heard rumors that a Neanderthal Institute director was going to introduce the speaker. I am that Neanderthal Institute director, Eric Green, director of the National Human Genome Research Institute, and I want to welcome you to actually a special talk that the institute is putting on, and shortly you'll be hearing from our special guest Dr. Svante Pabo. Dr. Pabo received his PhD from the University of Uppsala in Sweden, and he conducted his post-doctoral research at the Institute for Molecular Biology at the University of Zurich in Switzerland, and also in the Department of Biochemistry at the University of California at Berkeley. Now, if you fast forward, he is now the director of the Max Plant Institute for Evolutionary Anthropology in Germany. He's also an honorary professor of genetics and evolutionary biology at the University of Leipzig in Germany, and a guest professor of comparative genomics at the University of Uppsala in Sweden. And previously, he was full professor of general biology at the University of Munich. Now, Dr. Pabo is truly an authority on the study of ancient DNA. He was the first to successfully clone DNA from a mummy. His DNA sequencing efforts have determined that ancient bones come up from a previously unknown species of hominid called denisovins, which he's going to talk about. In 2009, he completed the sequencing of the Neanderthal genome in an effort that included a collaboration with Dr. Jim Mulligan, the director of the NIH Intramural Sequencing Center at NHGRI. And recently, his research has shown that Neanderthals interbred with modern humans some 50 to 80,000 years ago. This year, Dr. Pabo had a book come out entitled Neanderthal Man in Search of Lost Genome. And in this book, he explores the concept of what we can learn from the genes of our closest evolutionary relatives. It details his impressive portfolio of genomics research from the early 1980s to the present day, and also will notably explores the origins of modern humans and our relationships with Neanderthals. In February, his book received a glowing review from the journal Nature. In addition to his book, he's co-authored over 250 publications and his list of international awards and accolades is impressive. As an example, 2007, he was named by Time Magazine the list of 100 most influential people in the world. And various other awards decorate his very impressive CV. He was also recently elected to a member of the Royal Swedish Academy of Sciences, and he was also a Gruber Prize winner in genetics. It's been just a pleasure to have Svante here this week. He actually, two nights ago, down at the Smithsonian's National Museum of Natural History, gave a public presentation put on by the Smithsonian Associates involving a partnership between NHGRI and the Smithsonian Institution associated with our exhibition, Genome Unlocking Life's Code. And associated with that are a series of evening public events. And Svante was featured two nights ago as one of those events and it was really terrific. And he's even been more generous with his time. He spent yesterday at the Smithsonian giving a couple of talks, talking to their scientists. And then he's spending all day today here visiting NIH, giving this talk and visiting with NIH scientists. And then back tomorrow to the Smithsonian for more meetings before he gets to fly home to be with his children this weekend. So it's truly a pleasure to have Svante here joining us at NIH today. So please join me in welcoming a gifted scientist, a valued colleague and a good friend, Dr. Svante Pebo. Thank you very much. It's really a great, great pleasure to be here. I think it's 25 years ago when I was last visiting physically at the NIH, although we have collaborated a lot. And it's impressive the changes and growth that has been. Although it's much harder to get into the facilities now than it was 25 years ago. So what I wanted to do then is talk a little bit about the technical efforts in retrieving ancient DNA and sequencing ancient genomes. And then focus on what we have learned by studying genomes from our very closest extinct relatives, Neanderthals and relatives of Neanderthals. And for the last third of the time or so, talk about where we go from here, how we can use these genomes to try to get to functional differences between us and other organisms, particularly them, Neanderthals. But just as a means of introduction, I want to remind you about the fact that most of you are very well aware of that. If you look at genetic variation among present-day people, you find most of that variation in Africa. Whereas although there are many, many more people living outside Africa, we actually have less variation there. And not only that, there is almost all more common haplotypes anyway that you find outside Africa have closely related sequences inside Africa, but there is a component of the variation, so to say, in Africa that you don't find outside Africa. And the interpretation of this is that modern humans evolved in Africa, accumulated variation there. And a part of that variation went out and colonized the rest of the world. And by different tricks, looking at linkage disequilibrium, for example, in these haplotypes outside here relative to inside, you can estimate when that exodus out of Africa happened. And it's in the order of 100,000 years ago or less. So this is the basis of the recent African origin model for the emergence of modern humans. But there is, if you like, a problem with this model, and that is that 100,000 years ago, there were many other forms of humans around. Most famously, then Neanderthals in Europe and in Asia, other less well-described forms of humans. So here is a reconstructive skeleton of a Neanderthal compared to present day human. The Neanderthals were these sort of robust forms of hominins. They appear in the fossil record three, 400,000 years ago. And disappear again around 30,000 years ago. Generally, rather contemporaneously with that modern humans appear in an area. So there are two major ideas around in paleontology of how modern humans relate to Neanderthals and other extinct forms when they come out of Africa. One in this total replacement model says modern humans comes out, replaces these other forms with no mixing whatsoever. Another idea is that these modern humans that come replace the Neanderthals, but also mix with them and accumulate genetic variation from them to present day people in Europe and with other forms in Asia to present day Asians. So the first, so you could regard this as sort of a sliding scale from total replacement, zero percent contribution from these extinct forms of humans to more and more contribution up to total continuity that I think no one sort of advocates at least in 15 years or so. So the first chance to test this with genetic means then came in the mid 90s when we got access to this specimen, which is not just any Neanderthal, it's the Neanderthal from Neanderthal that was found in 1856 and gave its name to this group of hominins. And it was actually the first time I realized that there had been other forms of humans here before the present form of humans. So we then extract DNA from such specimens under sort of clean room conditions to avoid contamination from ourselves into the experiments. And at that time with the technology that was there with PCR was focused on a particular valuable part of the mitochondrial genome. Canberra's only amplifying it, cloning pieces, believing the substitutions that were consistently there. And if you then reconstruct a phylogenetic tree for this mitochondrial genome, you will find that all present day mitochondrial genomes go back to common ancestor a hundred, two hundred thousand years ago. And much further back, half a million years ago or more, is there a common ancestor shared also with the Neanderthal mitochondrial genome. So since then, we and others have sequenced many other mitochondrial genomes from Neanderthals, they all fall outside the variation of present day humans. So it's quite clear from this, there is no people walking around on the planet today with a mitochondrial genome from Neanderthals. So in this scheme of things, for the mitochondrial genome, it's total replacement. We of course learned something else from this too, and that was this age of around half a million years for the split of the mitochondrial genome of Neanderthals from present day humans. That suggests that the population split between what became Neanderthals and modern humans later, happened sometime after half a million years ago. So that of course already means that the Neanderthals cannot be very different from us. Because if I just compare two pieces of DNA into genomes today, the average time back to common ancestor from those two pieces is somewhere around half a million years, with a large variance around it of course. So there is no problem to find some pieces in the genome where I am someone in order to differ by a million years. So that means that also if there was no mixture whatsoever for the nuclear genome, it would be the case that for many parts of the genome, someone today would be closer to Neanderthal than someone else in the audience would be. And if we moved to another part of the genome, the situation would be different of course. But this then doesn't mean that the Neanderthal genome would be uninteresting to study, because there will of course still be parts of the genome where all modern humans sort of fall outside the variation of Neanderthals. And the opportunity to go after the Neanderthal genome then came with high throughput DNA sequencing, where you could leave this sort of trying to retrieve a particular little piece of DNA, but simply go and extract all the DNA you have in a fossil, process it, a sequence it all to exhaustion, create a little data bank, and start seeing what pieces of DNA here look human-like, so they might be from the Neanderthal, what is bacterial, and so on. So this worked for the first time in the cave site in southern Europe, in the cave in Croatia, this bone that is 38,000 years old. And the first thing you will see if you look at sequences from such a bone is that there are indeed short pieces of DNA here, 50, 60 base pairs, hardly anything approaching 200 base pairs. Also, it's only a tiny fraction of the DNA that actually counts on the Neanderthal. The vast majority, in most cases, 99% or more of the DNA comes from soil bacteria and fungi that have lived in a bone when it was deposited in the cave. So we started the project and we're very happy to get funding for an effort then to sequence the entire, the first sort of overview version of the Neanderthal genome. And during that time, we worked a lot on making the methods more efficient in how we come from a bone to a sequencing library that we can put into the sequencing machines. The machines in that time got more efficient in terms of how many molecules they could sequence. We looked through many, many sites, many bones, to find the ones with the most Neanderthal DNA in them. And it was in the end, three bones from that site in Croatia, from three different Neanderthal individuals that generated data for the first version of the Neanderthal genome. So we sequenced a bit over a billion DNA fragments, sort of mapped them to the human genome, having algorithm to take into account that there are typical types of errors in these sequences that you have to take sort of into consideration. And we had a one-fold coverage of the genome so that we had seen just a little over half of the genome once. But that gave us the first chance to start asking questions. And the first question that we were interested in was this, what happened when modern humans came out of Africa and met Neanderthals? Did they mix or not? So to address that, we did that in several different ways because this is a very controversial question. There were really sort of wars in paleontology going on about this. So I had the feeling that I had to get it really right. But one very direct approach to ask that was to say that if there was a contribution from the Neanderthals to people in Europe, we would expect people in Europe to share more alleles with a Neanderthal than people in Africa where there had never been Neanderthals. So it's this idea here. If there is no mixture whatsoever, then the Neanderthal is equally far from people in Africa as in Europe today, whereas here it would on average be closer to Europeans. So we went out at the time and sequenced five genomes. We would have exactly the same error rates, et cetera. One person from Europe, for us, of course, the archetypical European is a French person, so this is a French genome. Two African genomes, one from China, one from Papua New Guinea. And we did a very simple analysis. We are saying, if you compare now these two African genomes, find positions where they differ from each other, and then we take the Neanderthal genome and say, how often does it match one African or the other African? And since Neanderthals have never been in Africa, so there's no reason for a Neanderthal to be closer to one African than the other, it should be 50-50, which is the case, statistically speaking. However, if we compare a European to an African, we found significantly more matching to the European individual than the African individual. When we went to China versus Africa, we again find the same thing. And even Papua New Guinea, we see the same thing. So this was very surprising to us at the time, because if we would see a contribution, we would have expected it in Europe when Neanderthals had lived, not in Papua New Guinea and China, where they had not existed. So the question was, how could this be? And the sort of model that we had time suggested as the most plausible model that has since been born out by much other work, also from other groups, is to say that when modern humans come out of Africa, between 50 and 100,000 years ago, they're presumably passed by the Middle East, and we know they lived Neanderthals there. So if those modern humans mixed with Neanderthals and then became the ancestors of everybody outside Africa, they would sort of carry with them this Neanderthal contribution out into the world to the extent that people outside Africa today have something between one and 2% of the genome from Neanderthals. There has been, we now begin to know a little more about this admixture process also because it has been observed that in East Asia, there is actually more Neanderthal DNA, about 20% more, so say instead of 1%, 1.2%, than there is in Europe. And Josh Ake published a paper in Science in January where they modeled this contribution from Neanderthals once to the common ancestor of all Africans, and later admixture went affecting only the ancestors of Asians, and that fits the data significantly better. So there seems to have been at least two events of admixture here, one to everyone, one perhaps in Central Asia or something like that, that affect the ancestors of Asians. You may also ask, when did this happen? That was also important to exclude other scenarios. And an approach to estimate that came primarily from David Reis' lab in Boster, which takes advantage of this fact that if you have two populations like Neanderthals and modern humans mixing, the first generation hybrids will of course have one chromosome from Neanderthal, one from a modern human. If these hybrids then continue to live in the modern human population and mix with them, you will have recombination in each generation, of course. So this Neanderthal DNA will be broken down to smaller and smaller pieces as generations go by. So you can then use the size of such Neanderthal chunks to get an approximate age of when they entered the human gene pool. So you're looking at things like this. If you have European sequences up here, the variants are sort of indicated in yellow, the Neanderthal down there, you will find that some Europeans here are almost identical to the Neanderthal over some tens of thousands of base pairs and quite different from everyone else. So you look at the size distribution of these things, make some assumptions about mutation rates, generation times, and genetic recombination landscape and arrive at a date somewhere between 37 and 86,000 years ago, which fits with when modern humans come out of Africa. Now, this relies on a lot of assumptions, this modeling, and I'm, of course, always a friend of real direct data. So there is, of course, another way to go after when this happened, and that would be to go back to really early modern humans and see if they had mixed with Neanderthals or not. And it's beginning to become possible to do that, I think. This is a place in Western Siberia called a little town called Ostishim, where two years ago one found a bone on the riverbank here and this is this bone here that we have just recently analyzed. So this is not published yet. But we have sequenced this genome now to 42x coverage from this bone, and we've also carbon dated it. And to our delight, this bone turned out to be 45,000 years old, so it's clearly the earliest modern human outside Africa and the Middle East that is known and we have a good genome of it now. So if we now just look as an example here on one chromosome, chromosome 12, and plot here what comes from Neanderthals, in Europeans and Asians, you can almost see that there is slightly more Neanderthal contribution in Asia than in Europe, actually, when you look at this. And the question is this, now this 45,000 year old individual have that one mixed with Neanderthals or not? And the answer is that indeed it has, but we see a lot bigger chunks, of course, as we would expect back there. So we can now go and look at sort of correlations with genetic distance in present day humans. This is the data that leads to this date of 37,000 to 86,000 years ago. This is this 45,000 year old early modern human. And this leads to an estimate that it happened around 300 generation before this guy lived. So that takes us to somewhere in the order of 50,000 to 60,000 years ago. So we're sort of beginning to narrow in on the time point when this happened. Something else that we're interested in is of course other extinct forms of humans than Neanderthals. And we are very lucky to work together with Professor Derev Yanko in Novosibirsk and his colleagues, but Professor Shunkov, that excavated many places in Siberia, but particularly at this cave site there, in southern Siberia, the Nisova Cave, on the border to China and Mongolia and Kazakhstan and Russia where the four countries meet. So it's at this place here in the Altai Mountains, where they in 2008 found what they very skillfully recognized might be a bone from a human. It's a fragment of the last phalanx of a pinky of a child. So we sort of got this bone and extracted DNA from it and it turned out to be surprisingly well preserved. So whereas our very best Neanderthal bones have 4% Neanderthal DNA, this one had 70% endogenous DNA. So we went on and sequenced the first sort of overview of this genome. And to our surprise found that this Nisova finger has a common, the genome has a common ancestry shared with Neanderthals, but Neanderthals since have a long independent history. So the divergence between this individual and Neanderthals is substantially deeper than any divergence among present-day people here. So we sort of then named this sort of group of extinct hominins, denissivants after the first site where they were then found, just as Neanderthals are called Neanderthals after Neanderthals were first discovered. It's the first time then that an extinct group of humans is described just from a genome sequence. What we have happened since is that we have improved our methods quite dramatically for retrieving small amounts of damaged DNA. There are many little tricks to this, but the major trick is really a library preparation method where we use not double-stranded DNA that you add adapters to, but start by denaturing the DNA, by single-strand ligation add-on adapters with a biotin on them so we can immobilize them, synthesize the other strand, and then get something you can sequence. So this means that each double-stranded molecule has two chances to enter the library, so to say. So whenever you have some chemical modification on one strand that makes it impossible to replicate the sequence of molecule, the other strand still has a chance to enter the library. And when we sequence deeply enough, we actually see that we get both strands from molecules. So we've now been able then, we're then able to go and get high-coverage genomes from these things. So I have a 30x sequence from this finger bone here, where we then have very good coverage of the part of the genome we can map short fragments to, so say 1.8 gigabases or so of the genome. So what you can then do is, for example, begin to look at the time back to common ancestry for particular parts of the genome. You can look at the two alleles and see how far back they coalesce. And you can do that for hundreds and thousands of parts of the genome and look at the distribution of times back to common ancestry here. And with a method that Hengli and Richard Durbin have developed, you can then estimate effective population size back through time. And obviously, where you have more of these coalescent events is when the population have been smaller. So in this example, a dip here. So from looking at a single individual, you can estimate the population size history of the population that the individual comes from. So if you do this now for present day people from Africa, Europe, and Asia, you will see that everyone here shares, if this is a past, everyone shares a decrease in population size, an increase in population size. And only quite recently, since 50, 100,000 years, do we see a difference where Africans have a bigger effective size than non-Africans. And now we can look at this Denisova individual and look how that population history looks. And what you will then see is that if anything, it's likely bigger here, but then as it crashes down and goes extinct. So it's quite fascinating to me that the population history of this individual is dramatically different than anybody else that's around on the planet today. What you can also do when you have old, but high quality genomes is to begin to look for what we could call missing mutations. So an individual that died tens of thousands of years ago have had less time to accumulate mutations, of course. So in this case, if we say how many mutations do we miss here relative to the common ancestor to the chimp, it's a little over 1%. So if we now claim that this is 6.5 million years, which is very uncertain, but let's say that, this would mean that this bone is 60 to 80,000 years old. And this bone is, of course, so small so you cannot carbon-date it and you can actually not date it by any other means. But when we haven't, it's sort of, there are many caveats with this, I should say. We, of course, have different error rates in these present-day human genomes. So you actually see that the apparent age of these present-day humans vary by about 20% of this. There's something like 0.2% variance here back to this. But in the future, when we have even more accurate sequences, I think one can actually then date bones from genome sequences by this approach. Even bones that are then sometimes so small so you cannot use other physical methods for dating. You can ask for these denissivance, as the ponandatos have they contributed to present-day humans? And quite surprisingly, they have done so, but not very much in mainland Asia, but out in the Pacific. So Papua New Guinea, Australians, Fiji, and so on. So this suggests, presumably, that they were more widespread in the past so early modern humans mixed with them when they came to Southeast Asia, the ancestors of what is today the people in the Pacific. So I think this is sort of an indication of what will happen much more in archaeology in the future, that from tiny little bones, you can reconstruct a lot of the population history of individuals you find. But very frustrating, they have no idea how the skeleton of this individual looked, what stone tools they made, et cetera. But to just summarize before we come to the last part of the talk, about what we then think about the origin of neanderthals and denissivance first, we think they have an origin in Africa and come out of Africa and evolve in Western Eurasia to what we call neanderthals and in Eastern Eurasia to what we call denissivance. This is not to say that they were this widespread at any one point in time, nor that it was the only forms of extinct humans there. We don't really know what the border with neanderthals were, but at some time in these altimounties of neanderthals, at some other time, denissivance. Then modern humans emerge in Africa, come out of Africa, mix with neanderthals, presumably in the Middle East, and around 50,000 years ago, start spreading seriously over the world. They mix once more with neanderthals and perhaps in Central Asia, and they mix with denissivance, somewhere in Southeast Asia, and continue out into the Pacific. And then these forms become extinct, but they live on a little bit then, so to say, in people today, in that something like up to a maximum 2.5% perhaps of people's DNA come from neanderthals and you add another 5% here from denissivance in the Pacific. Now we sequence two extinct genomes and found two cases of admixture. I wouldn't be surprised if we find more, for example, in China, in the future, other forms that could also contribute to the bit, nor if there would have been contribution in Africa. So I don't think there's necessarily an absolute difference between Africans and non-Africans in that only non-Africans have this archaic contribution. But so we have clearly rejected this total replacement idea. We have a contribution from these extinct forms, but the major picture is of course still an exodus out of Africa, and most of our variation comes out of Africa. So the sort of term for this, I like to sort of suggest something like leaky replacement or something like that. There is a replacement, but a bit of genetic contribution from these other forms. So what's next then in this field? Well, one thing that was actually now just achieved a few weeks ago is that we now have a good Neanderthal genome also that we published actually two months ago now. Quite curiously comes from the Altai mountain and the very same cave as the Denisova finger, where deeper down in the stratigraphy in 2010, they found a toe bone. And that toe bone we obviously thought would be Denisovan. We went and sequenced the genome, but it turned out to be far away from the Denisova and close to other Neanderthals. So this is a Neanderthal, and we went on and sequenced the genome to 50X. So we can now look at that genome too. So if you just look at heterosagosity, for example, how much variation is there between the two versions of the genome here? If we compare present day Africans to non-Africans, we see this that non-Africans are less variation. And here are then the Denisovan and Neanderthal. So they have very little variation, extremely little. And not only that, if we look at this Neanderthal genome, we found something else. We found that there were huge chunks on the chromosomes that were identical between the two parents. So an example here of chromosome 21, whereas we don't see such long pieces saying the Denisova genome. This obviously indicates that the parents of these individuals were very closely related. So you can then model the relationships that these individuals' parents must have had. It must have been one of these four relationships. They were half-sib, say, or grandfather, granddaughter, or these other relationships that are complicated. I can't even describe them. But it's sort of quite interesting that we can get to some of the social things that went on in that cave sort of 60,000 years ago in Siberia. And it will be very interesting when we have high-caverage genomes from other Neanderthals to see if this is a general pattern in Neanderthal or something special for this population. We do see evidence of closely related ancestors also further back in the pedigree of this individual. It's not just in the last generation. So we then have these two good genomes here. We have one Neanderthal, low-caverage genomes from the Caucasus and the one from Croatia. So we can now begin to look at contributions not only to inter-presenter humans, but between these extinct forms. So if we do that here, modern humans, Neanderthals, Denisovans, we see this contribution from Neanderthals to non-Africans and from Denisovans to people in the Pacific. We now also, with the high-quality Denisovan genomes, see a tiny contribution to mainland Asia. So people in China have something like 0.2% Denisovan contribution. But we can also see that there have been genes flow from the Siberian Neanderthals into Denisovans. And quite interestingly, we find a quite old component in the Denisovan genome that we don't see in the Neanderthals that comes from something else, something that diverged earlier from the modern human lineage between one and four million years ago. So it's very tempting to suggest that this is homorectus in Asia, or something like that, that contributes to Denisovans. So it's very clear, I think, all these human groups have mixed with each other, but generally it's mixture of low magnitude. We don't haven't yet found something where 30, 40% have come from some other group. What you can then also do now is start to look more careful in present-day human genomes, in the 1000 Genomes data, for example, for contributions from Neanderthals. So there were two papers that appeared in January in Nature and Science, one from David Rives' group, where we were involved, and one from Josh Ake's group in Seattle, where one had looked at the frequency of integration in the 1000 Genomes data of Neanderthals pieces. And you will see that there are some things that actually reach high frequencies in humans, 70, 80%. So if you first ask what are those things that have risen to high frequency, what genes do we find there? The only functional group we consistently find are keratin's inherent skin. So something like that seems to come over and influence the phenotype today, perhaps. Already earlier, it had been shown from a group of Stanford, from Peter Parham's group, that MHC elites had come over from Neanderthals and from Denisovans, and sometimes reached high frequencies, presumably from selection, perhaps from pathogens or so. And in December, there was a paper published in Nature from the Sigma Consortium that David Altschuler is organizing, where they found a new risk allele for type two diabetes in Mexican Native Americans, a lipid transporter, but the risk allele carries four amino acid differences from the non-risk allele. And this risk allele occurs in East Asia and sometimes up to 25% or so native Americans. And if you make a tree of the risk alleles and non-risk alleles and put in the Neanderthals here, you will find that the Neanderthals fall right into that. So this is obviously an allele that had come over from Neanderthals into ancestors of Native Americans in Asia somewhere and risen to high frequency, perhaps because it conferred some advantage in starvation or something like that, and now causes type two diabetes. So some of these mixtures, where these archaic forms actually have, seems to have some phenotypic consequences. What you can also look for here is of course regions where you don't find contributions from Neanderthals. So you can look in present day genomes where for regions where you would statistically expect the Neanderthal contribution, yet you don't see it. So it seems to be negative selection there.  And if we ask what genes are located in such deserts, as we would like to call them, of Neanderthal contribution, where are those genes expressed? The only tissue that stands out with genes expressed in such regions are genes expressed in the male urn line in testicles. So it's very tempting to suggest that maybe the hybrids had some problem with male fertility, which of course is not uncommon when close related populations mix with each other, be that horse and donkey or what have you, that the male offspring is sterile and the females are fertile. So there may have been something like that going on. But to end then, I would like to spend a little bit of time on what I perhaps find as the most exciting sort of future development of this. And that if we can get to sort of functional things that are unique to modern humans relative to our closest relatives. So things that have changed here, which we can now identify when we have the high quality Neanderthal and the Nisman genomes that have changed here, yet spread to everybody today, no matter where we live on the planet. So things that happened here and became fixed in humans very recently in our history. And why are those sort of changes particularly interesting? Well, I do think that there are some things that have happened when modern humans came that have really set us off on a totally different historic trajectory, of course. So if you look at stone tools, for example, that the Neanderthals made 300,000 years ago when they appear and when they disappear 30,000 years ago, those stone tools look pretty much identical to each other. All technology across the whole range of Neanderthals is also pretty similar. When modern humans come, all that changes, technology starts changing rapidly and becomes regionalized in different regions. Modern humans make different tools and we have, after all, existed only a third of the time that Neanderthals have existed on the planet. And I think we agree that our technology today is quite different as 50,000 years ago. There are other things such as figurative art, art that really depicts things, comes only with modern humans and, of course, this thing that we spread across the whole globe. These earlier forms of humans lived for two million years in Africa, Europe, and Asia, never crossed water where we don't see land on the other side. Then come modern humans and in 50,000 years, one colonized not only America's, Australia, but every little speck of land in the Pacific. So the hope would, of course, be that some of this sort of reason for this very special thing that happened in human history would be hidden in this catalog of genetic changes that characterize present day humans. So if we now, just to illustrate this, take a very strict definition and say, what are the changes that happen here that to our best of our knowledge is in 100% of all humans today when we look at all databases we have access to, yet Neanderthals and the Nisvans look like the apes. Then that catalog is not a very big catalog of things. It's 31,000 substitutional differences, some insertions and deletions, and so on. So you can scroll through them in the computer in a few hours. So it's, for example, only around 3,000 regulatory regions. Now it's, of course, how you define regulatory regions, but if you take one definition of them, it's something like 3,000 changes. It's 96 amino acid changes, and I just focus on them for a second to sort of illustrate how you can go after this. This is not to say that regulatory changes are not perhaps even more important. So these 96 are actually located in just 87 proteins because some have several changes. And you can, of course, now start saying, could some of these be important? Hopefully there will be many experts on these genes that will sort of find interesting things here. We are, of course, biased to things that's saying things in the brain might be particularly interested. So we were quite interested when the Allen Brain Institute actually looked in different parts of the developing human brain and looked at these genes that have amino acid differences, how many of them are expressed there, and there's a control genes with silent changes that don't change amino acids, but otherwise are resentened in exactly the same way, fixed in humans, ancestral inandotoxin, and so on, and found that only in the proliferative zone where the stem cells divide to make new neurons, do we see significantly more of these amino acid proteins that have changed amino acids expressed? And these are, of course, signals that rely on few proteins. It's actually relies on five proteins, that signal, and quite strikingly, three of those five proteins are involved in the kinetic core and in the spindle. That surprised me a lot, but there are, of course, indications that say the mitotic cleavage planes of the stem cells in this epithelium when neurons are born determine, say, how many cell divisions you have and what types of neurons you make. So this is just sort of idle speculation that perhaps these three proteins should be particularly interested in studies in brain development, what these changes meant. But that brings us to the last question that I had, and that is this question, how should we go after these types of changes that are essentially fixed in humans, yet are perhaps involved in human-specific traits where we, per definition, have no sort of animal model? And I've gone around for years making jokes in the talks like this and saying what we want to do is take the Neanderthal allele and put in a transgenic human and the human allele in a transgenic chimp and said that we can't do that, of course, or we have to think about something else. But now it's suddenly not so ridiculous anymore because there is people like George Church, a professor at Harvard, no less, that go around and it's even more extreme like this and say we should clone the Neanderthals, we should put in all these changes in our catalog in a stem cell and make an individual. And I don't know why we are sort of forced to discuss this, I think it's technically impossible and ethically unthinkable, of course. But it doesn't sort of solve the problem, of course, we sort of, how will we go after these things? And I think that one thing that will happen soon, but people here are much better positioned than me to think and discuss this, is to say that I think in the future we'll be able to find back mutations in humans when millions of people will have a genome sequence when they go into the doctor's office. We'll, of course, know that all mutations compatible with human life exist in the human population because the genome is small enough and we're enough people there. But I think it will probably become ethical possible to find ways to go out and sequence and study these individuals, but that's a better way. You can engineer these into IPS cells, of course, and we and others are in the process of doing that to study differentiation of cells in vitro. And what I want to make a little bit of propaganda for the last three, four minutes, is then that one could perhaps after all use model organisms such as the mouse. And I want to illustrate that with one gene that we have studied since nine years now, it's a gene called FoxP2 on chromosome seven here. And it caught our interest because it encodes a transcription factor that when one copy is mutated, it's not only to severe language and speech problem in human families. It's also a very conserved protein that's encoded. So if you look in the mouse, it has only one amino acid difference here all the way to the chip. But interestingly, two amino acid differences on the human lineage there. They are close to each other in one exon. So it seemed very interesting first of all to look in the Neanderthal genome and Denisovagino to see if these changes are shared with them. And indeed it turns out it is. So these changes are carried also by Neanderthals and Denisovans. So they happen back here. So they are not a modern human specific one, but they are still interesting of course if they have something to do with speech and language with human specific traits. So what we have done already some years ago is to engineer these two changes into the human, into the chimp FoxP2 gene. So since this is such a conserved protein, we now have a mouse that essentially makes the human protein from its endogenous FoxP2 gene with one other very conserved change over there.  So we tried to speak to the mouse, but it didn't lead to anywhere. So instead we said this is a very conserved protein. So it could be anything in the phenotype really. So we were very lucky to work together with this mouse clinic in Southern Germany that do a very comprehensive screen of then the homozygous knock-in mice with their litter mates that are wild type. So do look at very many phenotypes as to give you a feeling for it to sort of going through them here. Hematology, what have you, eye function. All in all, they looked at 323 phenotypic traits. Not at all all independent of each other. Many are of course highly correlated, but it's still a very comprehensive phenotypic screen. We had two independent knock-in lines we made and there are only two phenotypes that were significantly different between knock-ins and litter mates. The first one is that the humanized mice are slightly more cautious in a new environment. Measured so that you have a social group here, you open doors and the mice can go in and explore an open area. Mice feel more safe along the walls. So the humanized mice stay at the walls, whereas the other ones do mostly that, but also venture in the middle here. But it's just a transitory phase. It's just the first few minutes are slower to explore the middle of the open field than the wild type mice. I have no clue what this means whatsoever. The other phenotype though arose my interest and that is that they vocalize differently. There's no way to say they vocalize in a more human-like way, but they measure that by taking two weeks old pups out of their nests and the peep in the ultrasound area here and the mound comes and brings them back into the nest. And there are a number of features in these sonograms where the humanized differ from the wild type. Sometimes it looks like sort of a dominant trait, sometimes co-dominant. So this is very interesting. It's sort of support that this changes might have something to do with muscle control and the oral pharynx or something like that. But the frustrating thing is that there is sort of hardly anything known about the neurobiology of mouse vocalization, of course. But you, after all, now have an animal model. So you can take out neuronal precursor cells, for example. You can differentiate them in vitro. And you will find here that if you do that from the stratum, they actually grow out longer neurites. So things that would become dendrites and axons. And in the live animals, you can also see bigger dendritic trees in the stratum. You can do electrophysiology in slices from these things and you can see that long-term depression where sort of the neuronal excitability goes down after a high frequency stimulation, sort of model for learning and memory is much stronger in the stratum in the humanized mice than in the non-humanized mice. So what we then know about this, it alters vocalization, you have more dendrites, you have this increased genetic plasticity and you have decreased dopamine levels that I haven't mentioned. So it sort of generates a hypothesis. The reasonable hypothesis is that we would have something to do with corticobasal ganglase circuits. Where the basal ganglase receives input and gives output to the cortex and the brain stem that has to do with motor learning often. And there are other sort of things that support this, the readings in the brain where we see this bigger dendritic trees. Just very recently then, a previous graduate student have worked with Anne Greyville at MIT and looking at motor learning in these humanized mice. So they do different tests where the mouse have to sort of learn to go towards a signal to get some reward that can be a tactile signal here or a visual signal. And under certain paradigms, these mice learn in seven to eight days what the wild type mice will take 11, 12 days to learn. And by doing various variations of this, this is not my field, I just relate what they have found. They have sort of made it likely that this has to do with a switch from sort of what they call a declarative phase of learning where the animal needs the cue, nose, it goes towards the lamp. And then after a while, you can stop turning on the lamp and it will know it will go to the left. It will sort of come to a procedure phase where it's sort of endogenously know I just turned left to get my reward. So they illustrate this to me by saying if you think about how you learn to bicycle in the beginning you think about how you bicycle and you're very bad at it. And then after a while you sort of automated it and you get very good at bicycling. And this correlates with activity shifts from the medial part of the striatum to the lateral part of the striatum. So this generated sort of hypothesis that we would see some difference in synaptic plasticity medially and laterally. So we then went back and did the electrophysiology in the mice and in the lateral part of the striatum we see this increased synaptic plasticity, increased LTD whereas when we then look medially we see no effect at all or if anything an effect in the opposite direction but no significant such effect. So this then seems to sort of support the current hypothesis that these amino acid changes have something to do with changing corticobase or granular circuits to make for faster proceduralization sort of automation of learning and perhaps then with aspects of learning speech and language. And you can of course make a nice sort of speculation and say what we learn to do when we learn to speak is that we automate coordination of muscle movements in oral pharynx to produce articulate speech. And it's probably the most sophisticated muscle coordination that we actually do in our life. And a form of thing that say apes are not able to do. I should accelerate a little bit here. I should just say in the FoxB2 gene we also find a regulatory change it seems that is very conserved all the way to frogs yet changed in modern humans. And it affects the PAL-3F2 site where we can show that ancestral version actually binds less of the dimer and also it's more efficient in driving expression in the model system. But we don't know anything more about that but it somehow seems that we have these amino acid changes and perhaps a regulatory change then there. So this is a lot of work over several, several years of course and in the end we sort of have to study these changes I think in this systematic way back into the organisms to then hopefully maybe in the end understand something of what set humans on such a very special track among all other primates. So I hope I sort of convinced you that if you're interested then in human evolution and recent changes in humans it's very good to have the genomes or closest relatives because you can sort of see what have happened on this line here in the future also here when we have more genomes here but it will not be enough to have the genomes. The genomes are just a two locals what we have to do in the end is sort of functional work and I think the most reasonable well forward there is after all a humanized mouse. So there are many people involved in this many more than I can mention I'd already mentioned that in the analysis consortium Jim Mulligan and his group here played an important role. I also want to mention just one person Mattias Meyer and the group that came up with this single stranded library protocol that really made it possible to generate these high-caverage genomes from these extinct forms of humans. And with that I thank you for your attention. We have microphones in each aisle and so if people have questions I'd ask them to please go to a microphone. Yes? You mentioned at the beginning that mitochondrial DNA did not support a mixture hypothesis. And later you said that wouldn't this imply that the DNA from the Neanderthal was male? Yes, so that would be one explanation for it. It's also compatible with that. This is just stochastic variation. The mitochondrial genome is inherited as just one unit. So it's rather easily lost if a female has no female offspring it's sort of her lineage is lost. So the more boring explanation is that. We also see on the X chromosome reduced contribution from Neanderthals. When we first saw that I said that's clear. It has to be male gene flow because males transmit only to have their children that transmit an X chromosome. The other ones get a Y. But then we've seen these sort of deserts in other chromosomes too. So that made us shy away from saying that this is male gene flow. But if I would guess I would say it's mainly males. Okay, and doesn't this conflict with what you said later on that Neanderthals had less, probably less fertility? Well, the hybrids would have had less fertility. So I think in the hybrids this would suggest that the female hybrids may have been fertile but the male hybrids may have reduced fertility. In the analysis that led to the testes specific genes standing out in speciation and model systems heterochromatic regions can be very important. So do you see any signals pointing you towards those non-genic regions? The only analysis we have done is that in these deserts what genes are enriched there. So there might well be, we would not have seen it as we have analyzed it. Much of the heterochromatic things are perhaps also repeated or so there we have really mapping problem from our short little pieces. So we can only statistically say how many copies of a repeat is there. We cannot really reconstruct the array of repeats. So Svante, it seems that you're trying to identify humans with back mutations as you called them is not a crazy idea. I mean it's absolutely gonna be probably feasible in only a matter of years if we can get all the data aggregated in a way you can look specifically. But when you, how are you imagining then taking that knowledge to sort of the next study?  I would after all hope that one would find this in cohorts where we recall possibility. And what would you do with those individuals? Well that of course depends on what gene or what regulatory element is affected where you would get a phenotype. So you'd want to win that with some functional insights. Yes, I would imagine that, yes. And before we get to that, I would propagate that on genotyping arrays these are just 31,000 SNPs. Why don't we add them to genotyping arrays today so we can pick them up quicker actually? I'm a little troubled to understand that your statement that Neanderthals didn't exist in Africa at all. They came out of Africa 300,000 years before none of them stayed or they only developed or they radiated, they couldn't walk back to Africa. So it's my sloppy language I guess. It's the ancestors of Neanderthals that come out of Africa. So there are things that Neanderthals we call homohydral burgansis that you see both in Africa and outside Africa. And the idea is that they evolve into Neanderthals. But the morphology we use to define Neanderthals is never seen, that's something that appears in Western Eurasia. And we now have a little bit of DNA sequence from the homohydral burgansis at 400,000 years old. So we begin to be able to reconstruct this perhaps. The DNA evidence is, I can see that link being there, but the fact that we haven't found a Neanderthal in Africa, it could be found tomorrow. Yes, but I would still be surprised if one did that because yes, there has been, after all, quite a lot of things found also in Africa by now. Okay, well, we have one more question. Last question. Just quickly, the Fox P2 story is so compelling. Are there any other kind of specific gene function stories that are evolving in your lab or elsewhere? Well, so we are now trying to put in a few others of these more recent changes into mice. Three of them that we sort of bet on will have some phenotype. There are other studies in mice that have come along that has been this Idar gene that has to do with sweat glands and hair structure that's a variant among humans today that have been put into mice and gave a sort of reasonable expected phenotype and even expectation of phenotypes that they then could go out and check in the human population and find them. So I think it's not unreasonable to suggest that mice can be for some things a good model, but it has of course its limitations. Okay, well, please join me in thanking Svante for just a terrific presentation. Thank you.


Hey, what's up guys? I hope you're doing super well today. I'm sure you've heard about this NAR antitrust lawsuit going on right now. Basically it states that there's specific rules that NAR has in place that creates a price fixing situation with the buyer agent commission. Okay, so I want to dive in on this. I want to give you my opinions. I'm hoping that my opinions really kind of eases the pressure for you on this. I don't think this is a big deal whatsoever. And there's a lot of people out there that are stating that they feel like commissions are going to be cut 50% if this thing goes through and that buyer agents are going to go away.  That's going to be dictated by the market itself, what our value is actually worth. And I think the market is speaking loud and clear. As far as buyer agents, they're here to stay. People need representation, want representation and will continue to have representation regardless of what happens here. So to say that commissions are going to go down 50% and there's going to be no more buyer agents, that shouldn't even be part of the conversation right now. Okay, so the reason I haven't made a video about this yet is because this has been such a non-issue for me. And the reason I'm doing it now is because so many agents are reaching out to me kind of freaking out about it. So I figure let me go on here and express my opinions on this, maybe give you a different perspective so that you can just carry on with your career here and go out there and crush it. I'm also going to start doing question of the day here on these videos. Today's question comes from Jamie Butler in New Hampshire. This is from Instagram. She says, hi Ricky, I need your help. I have some buyers who can't get motivated. Some even have their pre-approval letter and they won't make a move. I don't really want to be pushy. What do you recommend that I do? And I responded very quickly here. I said find other clients but stand close touch with these clients. You can't make people do stuff. Let them do the deal on their timeline. Your job is to help them, not push them. So I think this is very interesting how agents feel like they have to try to do something to get people off the fence. No, that's not your job. Your job is to help them through the process and people know when they want to buy or sell. It's not our job to help them figure out when to buy or sell. The reason why I've closed so many deals is because I do the deals on their terms. I help them do what they want to do. I don't try to get them to do what I want them to do. There's a big difference here and I feel like this has been one of the big pinnacles of my success because through that process of allowing them to do it the way that they want to do it has helped me create such a strong connection with my clients that they know that I'm not going to try to get them to do anything and they like that. They love an agent who allows them to do the deal on their terms. The real problem here is pipeline. You're going to have 15 to 20 active buyers and sellers at all times to close one deal a week. You want to close one deal a week? You have 15 to 20 active buyers and sellers at all times. If you're thinking about switching brokerages and would like to work directly with me and my organization, I would love to set up a call with you. We have a massive success rate with new agents, experienced agents, team leaders and brokers. Just shoot me a message on Instagram or email me ricky at zero to diamond.com. Let's dive into this lawsuit. The first thing I want you to realize is how incredibly grateful you need to be that we even have MLS and the way that it's set up and the efficiency that it brings to our industry. A lot of countries don't have it. They have open mandate listings, which means the seller picks eight different listing agents and the first one that brings the buyer wins and all the rest of them lose the deal altogether. We're incredibly blessed to be in the situation where we can do an exclusive right to sell, put it on MLS, and then the entire population of agents in our market are fighting to go sell it for us. We need to be thanking our lucky stars that were in this situation to begin with. Now, without being said, there's always going to be people out there with something like this that says, that's not right. You can't do that. That's no way. That's against the antitrust rules. Now, the argument here is that sharing of commissions between listing and buyer broker violates the Sherman Antitrust Act by inflating seller's cost. Are you kidding me? Absolutely not. That seller agreed to that commission regardless if there's a buyer agent involved or not. They're going to pay me that five, six percent, whatever it is, regardless if there's a buyer agent involved. What should it matter? It's kind of like a contractor. When they work and deal with a homeowner to do a project, they have a subcontractor come in and do the work and they pay the subcontractor out of the negotiated price with the homeowner. How is this any different? I love what one of Edmunds' publishers, Bernice Rawl said. She's also the CEO of Broker Jump and realestatecoach.com, but she called these lawsuits against our Duds. Now, she did say that there are some problems and that we need to make some adjustments in terms of the rules and however things addressed, which I 100% agree. Now, what's so funny here is that I was at Inman a few weeks ago doing a breakout session and Bernice actually heckled me. What's the number one reason why a buyer or seller chooses a particular real estate agent? What? Narnana study and it was that they had a friend in the business with a great reputation. Yes, ma'am? That's not the correct answer. Actually, 80% of the most recent profile of buyers and sellers shows that 82% of the sellers only interviewed one agent who they hired. The first person who gets to them when you're ready to transact is the one who will get to deal. And I would fear to say that if they had a friend in the business, that's probably going to be that first call, right? They have, well, I understand. I understand. Thank you. So for my business, not the rest of the industry, let's just say, not the rest of the industry, just my business. Right? I've created friends in my market and they use me and only me, right? And I teach other agents who do the same thing and they've been highly successful. We have a guy that's 20 months in. He closed 100 deals in his first 20 months. Two agents close 10 million in the first two new agents in the first year close 10 million in the first year just by doing what I'm talking about. What's the definition of a lead? What would you say, ma'am? Is the definition of a lead, ma'am? The definition of a lead, I'd call it to hear from definition of a lead. A lead, there are certain different white people categorized cities, but some people, you know, for me, a lead is someone who's either raised their hand that they're going to, they're interested in purchasing or listing. Got you. My definition is any human being in the market because the fact is, is that the humans who raise their hand are human and if they're not raising their hand now, they're going to raise their hand at some point. And if I have made the connection, had a real live conversation with them and they're marketed and branded to them in a way where I'm showing them who I am as a person that I care about them, there's a good chance that when they raise their hand, they're going to be raising it to me, right? So I'm just trying to collect humans, right? Leads are humans. So here's what we know. All closings originate from relationships, the more relationships you have with people in your market, the more closings you'll have. It's not official, guys. Now, as this was happening, I had no idea who this was. This lady is a legend in the industry. I talked to her for a long time after the session and she's a great, great woman. Now back to the lawsuit. This has nothing to do with the amount of money agents make, the percentage of commission or if there's even buyer agents. And I would argue that if there ever was a scenario which I don't believe ever would happen where buyers basically had to go through the listing agent, we would still be five, six percent, whatever it is that we charge now, whatever the normal is, because even in that instance, we're still representing, there's two people involved and we're doing twice as much work and we're juggling more balls, right? It's going to be really, really tough for this to happen in a manner that really decreases commissions, just not even, it's not even part of this. Now, the rules that are not having place that we're fighting over here basically states that if you're a listing agent, you put a property in MLS, you have to put a buyer agent commission in there and that that commission cannot be negotiated, right? And they're arguing that this is where the price fixing is. This is where the price fixing problem occurs. Now, again, my fault on this is very simple, okay? Even if this went to the very worst case scenario, not a lot's going to change. Sellers are still going to opt in to pay that buyer agent commission, right? Especially when they see other sellers doing it, right? There may be a shock to the system, but everything's going to pan out, the dust is going to settle, right? Let's say that doomsday happens and the seller can't pay, right? Never happened. Let's say it happens, the seller can't pay, right? Out of that listing side commission, the buyer has to pay their own fee, okay? In that scenario, you may say, well, buyers can't afford it and you can't figure it into the loan and all this and that. Listen, if something happens to that capacity, it's going to be figured into the loan, right? I think that in that scenario, all right, the banks are going to go back and there's going to be new roles in place, right? This actually going to allow that to happen, right? So there's a lot of different scenarios here. At the end of the day, nothing to worry about. We need to keep doing what we do best. Go out there, build relationships, help people, buy and sell real estate, continue doing what you know you need to do. If this is your first time seeing me, my name is Ricky Karuth. I've been selling real estate for 20 years now, right here in Gulf Shores, Alabama. I've closed over a thousand deals and I just love to help agents. I created a free real estate coaching program at zero to diamond.com. Go there, check out the 60 day challenge. Let me know if there's anything in the world that I can do for you. I'm here to help you and reduce the failure rate in the real estate industry. We'll see you guys on the next video. Let's go.


What's up internet? Mag-shop tour tayo ngayon. Pero in business sabihin namin what to buy yung baliktad. Sa sabihin namin what not to buy. Yung mga nice-to-have items, pero kung gipit yung budget, pwede naman tanggalin. Pwede na hindi pinin. Yung hard-wrestle girl lang talaga yung shop na sasabihin sa'yo na don't buy it. Bad for business, good for you. Let's do it. Pwede kailaw na windows. Pero saan ko hukawa nang legit windows? Daming options, daming prices. Aka nito. Pwede na lang. May cdkeyoffers.com. Wadalilo ang order. Search for the software you need. Add to cart. Daan ka sa payment options nila. Wala pag 5 minutes finished. May legit, working cdk na para sa windows mo. Gamitan ng aming code para makakuhapan ng discounts. Kaya kung nagahalap ka ng legit, mura at original software. Check it out, cdkeyoffers.com. Kung nagtataka ka, bat ako na ka-headset boong time sa video na to. Kasi li-nive stream ko yung shoot ng video na to. You can actually see the entire live stream kasama din dun sa links in the video description below. May dalamang klase na CPU coolers and if you're thinking water cooling and air cooling, you'd be right. Pero for the budget conscious, kung dalamang klase ay stock coolers na libre and third-party coolers na may dagdag gastos. Lahat na mga third-party coolers are made by a different brand from the one who made the CPU. Usually, mas makatan naman talaga yung performance ng stock coolers. That's why brands like Noctua are legendary. Usually, maganda rin yung aesthetics ng third-party coolers. Everybody loves the LCD screen of the Z-Series of Kraken from NTXT. Mga naman yung LED's nung capellix. They really crammed a lot of LED's here into the pump head. Or just the overall striking design of the galahad. Yung third-party coolers really deliver on performance plus aesthetics. Pero kung wala talaga sa budget, you don't need to get a third-party cooler. Most CPUs come with a stock cooler. Kung AMD, magadeng performance ng stock cooler ng AMD in fairness. Yung aesthetics din may RGB din siya. Kahit yung walang RGB na CPU cooler ni AMD Descentating nan. So really, props to AMD. Sila talaga yung parang nagpush na kahit stock cooler, ganda naman natin both performance and design wise. Yung Intel, well, yung performance yung Intel stock cooler may yung aesthetics ni Intel stock cooler walang RGB at mo ang throwback pa to the 1990s. Wala pa talagang nagbabago dun. So yung Intel CPUs may stock cooler naman you really pay for what you get. It will get the job done but barely. It's true yung mga high-end CPUs like the R9-5900X or the i9-12900K wala talagang stock coolers mga yan. You'll need to buy a third-party cooler. Pero if you're at that level, siguro may budget ka naman pambili nung stock cooler because you're not playing around when you get to that kind of CPU. Tugol sa CPUs, mapapansin mo pang pamahal ng pamahal yung CPU yung madami yung cores niya. Yung pinaka top-of-the-line yung Intel the i9-12900K 16 cores. Gunon din yung top-of-the-line yung AMD, Ryzen 9, 5950X 16 cores. Pero kailan mo ba talagay yung extra cores? Depending kung saan mo gagamitan yung computer mo baka naman hindi. Some applications like gaming don't really take advantage of the high-core count. So for price-to-performance mas maganda pa actually yung mas mura na CPU. So for gaming, if budget is a little tight we would recommend getting the 5600X which only has 6 cores compared dito sa Ryzen 7, 5800X na 8 cores. Makamura ka nung mga around 3,000 pesos, mapupunta pa yung to a better GPU which will impact your gaming performance more. Yung PC na gamit ko pang larop, pang edit, pang stream i54690K apat na cores lang siya. And yet, it gets the job done. Lahat nung kailang kung gawin, nag-agawa naman yung. Don't get me wrong kung may budget, mas maganda naman talagay yung higher-end CPUs mas sabilis naman sila. But price-to-performance, depending on what you're doing, di mo naman talagakailangan sobrang daming cores. Mahalagang consideration din yung price-to-performance in choosing RAM. Sa RAM, may dalawang options. The size and the speed. For the size, usually rin na-recommend namin 16GB. 12GB is the sweet spot for price-to-performance. We really only recommend 32GB or even more, kabag alam namin gagamiti ni customer yung computer pang server-type functions or heavy multitasking or 4K editing. O dami, ibang customers din kami na nagsabi na nararam naman nila yung different sa gaming pag nakakat 32GB sila. No question, your PC will run faster. Pero yung akong gipit sa budget, actually kung gipit sa budget, 2x4 or 8GB is usually what they get. But we recommend going a little bit further. Mararam daman mo yung difference at 2x8 to 16GB. Dun sa speed nung RAM, actually sa ibang in some situations makakasama pa yung kung sobrang bilis nung RAM. I've mentioned in a recent video the sweet spot for the Ryzen series is around 3800MHz. Lampas dun, baka makkasistem instability pa. Sa RAM, faster is not always better. At talon mo, from say 3200 to 3600MHz, yung price to performance medyo alanganin din. You'll pay around 10% more for a 3600MHz RAM roughly. Pero yung corresponding performance gain mo, hindi siya akit by 10%, mas mababa siya. Kung gipit talaga yung budget, large RAM and fast RAM are nice to have, but you don't really need them. Next up, SSDs. Palagi yung advice namin, regardless of the build, get yourself an SSD. Sobrang laking tulong nito sa quality of life mo. Ang bilis nung data access rate, ang bilis mag-boot up nung OS kung naka SSD ka. Para kaming sirang klaka dito sa hardware sugar, we're always saying get yourself an SSD. But make sure it's a SATA SSD. Basically ma SSDs come in two flavors, SATA SSD siya ka M.2. May dalawang klase nung M.2. So not all M.2s are NVMEs, but all NVMEs are M.2. Sintilan, diba? Para lang madali, isipin mo nalang that the NVME M.2 is the fastest kind of SSD that you can get. Pero yung price to performance niya, hindi naman ganun ka layo from a real world perspective dung sa SATA SSD. Nais to have yung NVME, pero kung di naman kayo yung budget, yung NVMEs kasi sobrang mahal niyan depending on the brand, depending on the size, depending kung PCI-E4 sila. Although before we leave SSDs, kailang ko rin banggitin na may mga sobrang murang NVME SSDs ngayon on the market, na good quality din naman. For example, itong team group na 256GB NVME SSD MP33 model. This is 2400. The ZOZT SATA SSD is 17. So that's around 45% or so increase in price. Pero in actual peso terms, wala pang 1000 pesos yung increase dito sa NVME. Dependit talaga yung sa budget mo kung ok na, sige, dagdagan na lang natin ng 800 para maka NVME. Sulit rin naman to. Kung kaya naman yung budget na plus 800, di ko rin masabi sayo to go with the SATA SSD kasi yung trade-off naman worth it. So that is something to keep in mind if you're shopping around for storage. Namay mga murang NVMEs relatively. Pero kung parang mo dun sa SATA SSD mas mura pa rin talaga yung SATA. Let's go back to cooling. Yung mga cases may points inside them where you can't mount fans. Usually these come from third party manufacturers kagayon ng mga CP coolers na pagusapan natin. Although may mga case manufacturers naman, nalagbabenta rin nung fans nila. For example, like Deep Cool, NGXT, Corsair. Magdadag ka nung case fans para mas malakas yung air flow in mas malakas yung air flow out para lumamig yung rig mo, the more air that's circulating, the quicker mawawala yung init nung mga components. Pero para sulit sa budget, pumili ka nung case na may kasama ng fans kung baga included na siya dun sa price ng case. Kagayon yung fractal design torrent case, 5 fans na kasama yan, may fan hub pa 12,400 pesos lang. Sulit, di ba? Pero a more realistic case might be this one, the Matrix 43FS, this is around 2400 pesos, may kasama ng 3 120mm static RGB fans. Maramin ng options sa market na may mga cases na kasama na yung mga fans. Ah RGB. Maraming na mawili sa RGB. May nagsasabi na hindi kompleto yung mga rig nila, hindi kompleto yung mga build nila, kung wala ng RGB. May nakakawento nga kaming customer na paminsan binubuksan lang nila yung computer nila para matingnan yung RGB. Not for work, not for play, just to see their RGB. And personally, ako wala ang problema yan. RGB is aesthetic, especially kung maganda naman yung pagkagawa, di masyadong over the top, it really adds something to the build. Pero yun nga yung RGB pang aesthetics lang talaga, kahit ilang ilaw sa loob ng computer mo, hindi bibilis yung performance, kahit ilagay mo sa blue yung RGB, hindi lalamig yung components. They're all just pretty lights. Kaya yung RGB yung last na suggestion ko, kung gipit talaga sa budget, pwede mo tanggalin yan. You don't need any RGB at all in your system. Ayon, thanks for joining us on our short shop tour of things you don't really need to buy. Kung nakatulong tong video na to, may ibang videos din kami, may build guide on how to build a computer for a 10k to 30k budget, may video din kami on how to build a good budget work from home PC. May video din kami, explaining ba't ka nagbabayad for certain PC features na hindi mo naman kailangan. Latong mga links to those videos are in the text description below. That's the video so now that may free time pa ako, manunod lang ako ng RGB. Thanks for watching. And thank you to our top fans na afford na namin to kupuwa na to, hindi joke lang. Thank you to Leah Magnaya, Ian Meru, ITX Addict, John Ruben Ocha, Christian Espinoza, and Raphael James. Thank you for supporting the channel.


I have to imagine you have been extremely busy since this lockout ended. How crazy have things been for you? As chaotic as you could expect heading into an office or a spring training after about a hundred days locked out from talking to your guys But all things considered it's back normal now, which is good to see typically you're connecting with players You're seeing video. You know where they are at. So how quickly can you evaluate where these guys are at? The nice thing is we've got a lot of returners So we kind of have a set expectations for a lot of these guys coming to spring training So I think we've got a baseline that we're kind of trying to meet and I think we feel like we're in a good spot overall Which is encouraging take me through it lockout ends. Are you immediately firing off texts? Yeah, we kind of got the word about seven o'clock that it was over and we send out a mass text like we're gonna get to All of you we just got to figure out, you know split these calls up and just basically don't have a lot of time To chat about how your off-season was where are you? What are you been doing? When are you gonna get to Tampa? Exciting moment when you think about the rotation yesterday, Luis Severino appears to be healthy He threw in a live VP session yesterday. What did you think of that? I thought it was encouraging, you know Just given where Sevilla's been at the last couple years to see how he did on his own this off-season in Tampa coming in ready to Go and you know bounce back well today So I think we're in a good spot with him with him considering the fact that he really hasn't pitched in two years What do you do as far as managing him and making sure that he's not? Over-exerting himself throwing too many innings back. Yeah, I think it'll be similar to how we managed a lot of the guys last year where we're gonna be Cautious in the onset, you know just making sure we're hitting all our benchmarks making sure he's recovering and then not gonna put a Necessarily number on him for say for the year But I think just making sure as each outing goes we're taking the inventory as he comes out and you know What's the objective information look like and you know nice things we got a lot of depth this year So you know not necessarily put the onus on him to cover, you know 200-plus innings if it doesn't mean, you know, he's not in that physical spot Could you see him maybe towards the end of the year being in the bullpen? Or is it something that you'll give him starts off throughout the course of the year? Yeah I think it'd be a combination of things where we're managing innings managing pitch counts managing days off and you know Just kind of seeing where we're at But you know, it's hard to say exactly what we would do at the end James and Tyone through today He's coming off that ankle surgery. How did he look to you? I look great I thought you know just given you know where he's been this off-season recovering with the ankle and then you know I would say on schedule You're just given that we're a little bit behind with the spring training and he's probably a touch ahead But you know, the Velo was good today 9194 and just given that you know and the shapes were good. I think we feel really good about that He almost seemed a little bit surprised with how many innings he was able to give you guys last year What would you like to see him do this season and taking a step forward? Yeah, I think just taking a full workload for him and I think you know just for him in particular It's you know bouncing back from the starts giving us the five six seven innings every time out and just see where we end up at The end of the year and I think less less concerned about you know What it's gonna look like given how he performed last year and stayed healthy till the end pretty much Do you worry at all about Garrett Kohler? Do you just expect that he is going to be ready to go. He knows what to do to take care of his body I don't worry about Garrett, but still give him, you know Respect in that he needs feedback and he wants to be coached just like anybody else You know just taking inventory and where he's at what he's been working on how he feels and I think overall like he's He's hitting his benchmarks as well, which is encouraging Jordan Montgomery seems as though he came in to camp a little bit slimmer What did he do in the offseason to achieve that and how do you think that could benefit him on the mound? Yeah, I think he just took his program serious and he's got a couple years under his belt now of the the programs that are in place here and Start of the year offseason in Chicago felt like it was a little bit too cold form and went back to his home in South Carolina and got a quality workload in both strength training wise the conditioning and also throwing I think he's obviously in a great spot. Nester Cortez played a major role for this team last year How do you see him fitting in this year? Kind of picking up where he left off I think for us it's looking at him as a starter until he's not and you know Just seeing how the other the spots shake out and the nice thing is he's versatile and he can come out of the Pen he can be a long guy you can match up with lefties He can start so there's a lot of ways to utilize Nester skills You have a lot of guys that are that are pretty versatile versatile Clark Schmidt Michael King Do you see them being in the fold this year? Yeah I think it'll probably depend a little bit on how the roster construction is to start the year with how many spots we have and you know Whether they're starters or coming out of the pen and piggyback and I think the nice thing is we've got some looks on those guys The last couple years so we kind of know what they are and both those guys that come into camp in great shape And I think the nice thing is we have some starting depth, but also they're they're comfortable You know pitching on a piggyback if needed So I think that the versatility will be big for us Dave Garcia struggled a little bit last year seemed like he maybe took a step backwards. What have you seen from him so far this spring? I know it's only been a couple days but I think looking like the the Davey of 2020 a little bit more so and we've just seen one bullpen so far But delivery looks like it's a better place the fastball life looks like it's coming back And I think he's you know less less concerned about what's happening over the rubber where he was last year and focus more on What's happening at the plate and I think that's a great spot for him to be in mentally Louise Hill got called up It didn't seem like necessarily that was in the plans But the circumstances dictated that you needed somebody What would you like to see him do to continue to improve? Yeah, I think it's I was a nice taste for him Both from a success standpoint and from a development standpoint of just seeing how his fastball plays in the zone And he should be aggressive with that and just work on you know pitch efficiency You know just to be an aggressive in the zone and attacking with his fastball and slider and Basically continue develop that change up along the way What are you most looking forward to this season a little normalcy maybe almost you would go a long way You know I think it's nice to have you know the media and the fans back in spring training So that kind of brings us back to pre 2020 pandemic times a little bit So I think the buzz is good around here and you know the energy of getting everybody back together after a long off season of No contact, so I think we're in a good spot. I just want to stay healthy and get out of the gates Well, wow you miss the media. We don't hear that very often We're gonna we're gonna keep that forever and remind you later in the season Matt, thanks for the time. No problem. Thank you