30 May 2012

Why a fat brain made us more vulnerable to heart disease

Natural selection granted us large brains. The evolutionary cost is having to feed them. The human brain's high-energy demands led to development of a strong preference for fat. We consume more fat than any other primate on average. We are also adapted to more easily digest and metabolize fats.

There are two major kinds of fat that our brains depend on most for its development and regular maintenance. These are the long-chain polyunsaturated fatty acids (LC-PUFAs), omega-3 docosahexaenoic acid (DHA) and omega-6 arachidonic (AA). These two LC-PUFAs can't be made de novo, making them essential in the diet. DHA and AA are supplied by seafood, eggs, or animals. They can also be supplied as their 18-carbon precursors alpha-linolenic acid (ALA) and linoleic acid (LA), found mainly in plants and their seeds.

ALA and LA precursors require conversion to become long-chained through a series of steps of desaturation and elongation. In particular, delta-5 and delta-6 fatty acid desaturases build onto the carboxyl end of the carbon chains of the ALA and LA by introducing double bonds. These converting enzymes are rate-limiting.

The rate-limiting enzymes are encoded into the genome by FADS1 and FADS2. The FADS region has been of special interest to researchers because of variations in single-nucleotide polymorphisms (SNPs) that could lend clues about human evolution including our larger brains. Yet, to date, there have not existed any studies evaluating FADS mutations among humans and related species.

Now, researchers from Uppsala University, in Sweden, along with scientists at MIT, Harvard, and major European Universities, have found genetic variation in the FADS region in present-day humans that made them uniquely adapted to biosynthesize DHA and AA. The same adaptations could also help explain why some ethnicities have a higher susceptibility to chronic disease today.

The international team set out to investigate by using genomic data from contemporary human populations, archaic hominins, and more distant primates. They used SNP genotype data from more than 5,600 individuals across five European population cohorts. They evaluated mutations in the FADS region that are strongly associated with omega-3 and omega-6 fats.

Two common FADS haplotypes

Among present-day humans, they report, exist two common FADS haplotypes, or groups of alleles defined across a set of 28 SNPs, that are "dramatically different in their efficiency" to biosynthesize DHA and AA from he shorter ALA and LA.
The 28 SNPs of two main haplotypes (A in red, D in blue) and nucleotides of species.

Haplotype A, limited in conversion efficiency, appeared nearly 606 thousand years ago. Rhesus monkeys, chimpanzees, gorillas, and Denisovans all bear haplotypes "very similar" to haplotype A. Neandertals too, although based on incomplete sequences, have similar haplotypes to haplotype A.

Haplotype D, having greater conversion efficiency, appeared somewhere between the lineage split with Neandertals. That was around 500 thousand years ago and before the exodus from Africa some 50 to 100 thousand years ago. Both haplotypes must've been present during the exodus or else we wouldn't see the existence of them in modern humans today.

The researchers speculate that "a very rapid increase in brain size of hominoids" probably involved selection and the increased frequency of haplotype D. That does not mean that haplotype D had any direct effect on brain size, but that it was highly advantageous in environments where there was limited access to AA and DHA to feed the brain.

Haplotypes A and D in Present-day Humans

Nowadays, the researchers found, nearly all individuals of African descent had haplotype D. The high frequency indicates positive selection for the haplotype with more efficient conversion in the face of limited availability of LC-PUFAs in early Africa.

On the other hand, nearly all Native Americans had haplotype A. The reason, the researchers propose, may be because of a "bottleneck effect in the colonization of the American continent, possibly in combination with relaxation of the selective pressure as a result of a diet higher in essential LC-PUFAs."

The data are mixed in those descended from Europe, Oceania, East Asia, who are reported to have haplotype D at a greater frequency.

The frequencies of A (blue), D (red), and mixed (gray) haplotypes.

Health Implications

How can the knowledge of these haplotypes inform guidance on diet? The differences in haplotypes may explain why individuals of specific ethnicities may be more susceptible to chronic disease compared to others.

Individuals with haplotype D biosynthesize more AA and DHA than individuals with haplotype A. While this adaptation may have been useful on the African savannah, the researchers propose it has drawbacks as a "thrifty genotype" in our modern world. As plentiful as LA (from corn and soy) is in the Western diet, haplotype D may lead to higher levels of AA-derived pro-inflammatory eicosanoids, which raise the risk of atherosclerosis and coronary artery disease.

A different set of problems are presented for individuals with haplotype A. These individuals may be protected against a high-LA diet to a degree because of limited conversion to AA. However, they are more dependent on animal foods for adequate amounts of DHA due to inability to convert sufficient ALA to the longer-chained counterpart on a more plant-based diet.

The researchers propose, "FADS genotyping should be included as a diagnostic for dietary recommendations."

As genetic testing is not yet widely available, here's a more viable solution for the sake of a large human brain and a genome not well adapted to a high-LA diet: eat less LA; and, eat more foods enriched in long-chained omega-3s such as eggs, grass-fed animals, and seafood.


Ameur et. al. Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain Omega-3 and Omega-6 Fatty Acids. American Journal of Human Genetics, April 12, 2012 DOI: 10.1016/j.ajhg.2012.03.014

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Tuck said...
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DC said...

This would be a great addition to 23andMe's genetic testing (just checked and, apparently, they already check 5 SNPs FADS1 and 20 on FADS2).

Tuck said...

The other logical conclusion is to eat less linoleic acids: less seed oils. Since linoleic acid blocks the body's processing of omega-3 fats, this is a necessary first step.

David Despain said...

Tuck, it makes sense to eat less linoleic acids. I covered the omega-6/omega-3 competition previously in my book review of Susan Allport's book "Queen of Fats" found here: http://evolvinghealthscience.blogspot.com/2010/01/book-review-queen-of-fats-by-susan.html

DC, Great idea about 23andMe

TipsandTrics.com said...

women over 65 who consumed the highest levels of saturated fats had worse overall cognitive function than those who consumed the least.
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Teech said...

Can you exlain why zoo gorillas here in the US are dying because of heart disease when they are on vegan diet? They aren't eating any animal products? The zoo keepers were feeding the gorillas a high sugar/starch diet, exactly what the SAD diet is. Hmm, it must be the animal fat that they are not eating . By the way, heart disease is their number one killer here in the US.