Why do African-Americans have increased cholesterol levels?

There is a well-established difference in cholesterol levels between Americans of European and African descent. In particular African Americans generally have higher HDL levels. HDL is known as the “good” cholesterol and has in many studies been associated with protection against cardiovascular disease. Curiously, African Americans generally have higher rates of cardiovascular disease – their high HDL levels do not seem to provide them much protection. Although socio-economic and environmental factors including diet certainly contribute, these factors alone do not appear to fully explain the difference. There appears to be genetic variants that cause African Americans to have higher HDL levels but less protection against cardiovascular disease. Finding these genetic causes is an area of much active research, and some studies suggest that the reduced HDL protection in African-Americans is related to paraoxonase activity. With the increase in GWAS studies focusing on African-Americans we will likely learn more about these factors within the next few years. But there is another question buried here – an evolutionary question. Why would there be differences in HDL levels and HDL functionality in different geographic areas of the world? One possibility is that it is purely random; genetic drift has caused these differences. A perhaps unlikely explanation, but an explanation that we nonetheless want to rule out before speculating too much about the adaptive reasons for the observed differences.

A new study from our group published in Molecular Biology and Evolution with Anna Ferrer-Admetlla as lead author, sheds some light on this. Behind the technical title “On detecting incomplete soft or hard selective sweeps using haplotype structure” hides a few results that might help us better understand the evolutionary underpinnings of HDL biology in African Americans. Using a new haplotype based statistic, we show that APOL1, the gene encoding the major protein component of HDL, is one of the genes showing the strongest signature of natural selection in Yorubans – a group from which most African Americans descent. We do not see a similar pattern in any other group investigated, including Maasais from East Africa. Most other groups show evidence for selection primarily in immune and defense related genes, except for the Maasais which show most evidence for selection relating to the lactase genes – a story that has already been investigated in great detail by Sarah Tishkoff. In addition, we find several other genes relating to cholesterol metabolism which also show strong evidence of selection in Yorubans, including CD36, a gene implicated in the binding and internalization of oxidized LDL (the “bad” cholesterol). So clearly, something serious happened evolutionarily with cholesterol in Yorubans. We can probably rule out that the differences in HDL levels and functionality between African Americans and other groups are simply a consequence of genetic drift – natural selection most likely caused these differences.

This then raises the next question: which phenotypes did selection act on? Without a time machine we will never know. Even though we can identify certain phenotypic effects of the genetic variants that selection has acted on, we cannot conclude that selection worked to change these specific phenotypes. Many, if not most, genes are highly pleiotropic – they affect multiple different phenotypes. Which of these phenotypes where the primary target of selection can be difficult to discern. However, one obvious explanation for the selection acting on APOL1 and other cholesterol related genes in Yurubans, might be changes in diet. Demands on cholesterol activity may depend on diet, and there may be trade-offs relating to the efficacy of fatty acid uptake, energetic costs, and risk of cardiovascular disease that have imposed different selective regimes in different parts of the world. While this explanation seems obvious, it doesn’t really explain why selection has targeted only people in West Africa. Many other groups around the world have experienced changes in diet. Our hypothesis is instead that the selection is driven by pleiotropic effects relating to defense against parasites. APOL1 is involved in parasite killing, particularly trypanosome killing. APOL1 triggers uncontrolled osmotic swelling of the lysosome in the parasite, an effective mechanism for elimination of parasites. Similarly, CD36 harbors genetic variants associated with susceptibility to malaria. The pathogenic environment differs greatly between different geographic regions, and West Africa has certainly historically been one of the areas of the world with highest parasitic load. So one likely explanation is that the selection on genes such as APOL1 and CD36 observed in Yurubans is in response to selective pressures imposed by parasites – not by changes in diet. When African Americans today have different HDL levels and functionality than other groups, it may be a byproduct of past selection acting on their ancestors in Africa in defense against parasites.

I decided to write this rare blog entry, in part because I wanted to draw attention towards these results from the Ferrer-Admetlla paper – results that otherwise might remain buried in the technical aspects of the paper. But this example also well illustrates the challenges in evolutionary biology in identifying adaptive causes. It is often quite easy to identify the footprints of natural selection in DNA data, at least when natural selection is very strong. We have a slew of good methods for detecting natural selection. Unfortunately, we will in most cases never know for sure which phenotypes were targeted by selection. Evolutionary biology is in part a historical science – and as such we have to live with some ambiguity: we can detect the footprints of past selection – but we may never know for sure which phenotypes selection acted on. There is not a simple experiment that can determine what happened in the past.

Familial [mis]identification rates and experiments in video

Happy to say that a paper I wrote along with Erin Murphy, Yun Song, and Monty Slatkin is out today over at PLoS ONE (and on the arXiv).  In the paper, we implement the familial searching method of Myers et al. and estimate power, false positive rate, and rates of distant relatives misidentified as near relatives.  Short story: we find very high power and low false positive rate, however we also see high rates of relative misidentification.

These results are relevant to people inside and outside of the scientific community involved in decisions about the implementation of familial searching methods.  With that motivation [and generally], I’m experimenting with explaining my research through different media apart from technical manuscripts.

Adhamh Hoeltzel, Alex Safron, Mosaic Project youth leadership, and I collaborated to make a charismatic and informative general audience video explaining the idea and impact of familial misidentification in social context.  I’m hoping to see this video used in high school classroom or other educational contexts to introduce ideas and stimulate questions about forensic genetics.

For a quick technical overview, I made a short video abstract which outlines the basic questions and results for a scientific audience (video abstract idea thanks to Eline Lorenzen, more information coming soon).

Finally, I wrote a guest post for Haldane’s Sieve to motivate and explain the work to population geneticists without background in forensic science.

I’m curious to learn how these different formats are received and see other scientists’ alternate-media projects.  Most importantly, I’m excited to see more engaged discussion of forensic identification methods and their implementation.

Clarence Thomas got it right!

I know – that’s a first.  The supreme court made a wise and unanimous decision on the Association for Molecular Pathology v. Myriad Genetics case.  You can no longer patent a gene. However, the supreme court upheld Myriad Genetics’ rights to patent cDNA from BRCA1 and BRCA2 – which might explain why Myriad Genetics’ stock jumped after the ruling.  Apparently, the investors had feared worse.  Exactly what a patent on cDNA entails may be up to future litigation, but it should not preclude many common genotyping platforms as a diagnostic tool for BRCA1 and BRCA2 mutations.

What are the long term consequences of the ruling?  We can probably expect private companies to invest less in basic research on the molecular genetics of disease.  It might be harder to make a profit on discovering disease related mutations.  On the other hand, it will be easier to develop new diagnostic tools based one existing knowledge.  We might expect a shift in focus in private companies from basic research towards development of diagnostics. That is not necessarily a bad thing.  But somebody else has to pick up the slack on basic research.

The mantra for funding of genomics research at the National Institute of Health (NIH) – the major funding body of genomic and medical research – has been ‘translational’.  Apparently, the phase in genomic research in which we focus on basic discoveries is over.  Now we need to focus on translating these discoveries into medical applications – diagnostics and treatments.  That is all good – but with the expected fallout of the supreme court ruling,  somebody has to continue the drive for basic research.  It is time for NIH to once again step up on funding for basic research in the genomic sciences.


Addendum:  Hilariously, while Scalia voted in favor of the ruling – he dissented on the basic principles of molecular biology. Apparently, it is not only global warming and evolution that is being challenged.  I expect soon to see a dissent on the shape of the earth or the placement of the earth in the solar system.


BAPG meeting in Berkeley Oct. 5th

The next Bay Area Population Genetics meeting will be hosted by our group at UC Berkeley on October 5th.  You are hereby invited.  Please
register and sign up for talks/posters at http://tinyurl.com/lglzosw.

For more information about previous meetings, see here.



Register for Bay Area Population Genomics

From Ryan Hernandez:
Hello Everyone,
We are excited to be hosting the 8th meeting of the Bay Area Population Genomics group at UCSF Mission Bay on June 8th!  Thanks to support from Ancestry.com and the Institute for Quantitative Biosciences (QB3 @ UCSF), this conference will include breakfast and lunch.  In addition, we will also have a reception during the poster session, so we highly encourage you to preview your work at BAPG before heading out to summer conferences.
Please register at http://tinyurl.com/a8h6uo8, and sign up to give a talk or poster.  Registration is again free, but required by June 3rd.
There is paid parking in the lot/garage at the corner of 4th and 16th streets, and we have a limited number of parking passes for people that sign up to present and/or make a strong effort to carpool (please email me for details).
We are very much looking forward to seeing you at UCSF in a few weeks!

This is an excellent opportunity to share ideas, learn about new topics, and meet other researchers! Unfortunately, this is the same weekend as the Miller Symposium that I’ve been co-organizing, but I encourage you all to participate.

Do it: 2013 Workshop for Young Researchers in Mathematical Biology

You know you want to go…
2013 Workshop for Young Researchers in Mathematical Biology (WYRMB)
August 26 – 29, 2013
Application deadline: May 1, 2013
The workshop is intended to broaden the scientific perspective of young researchers
(primarily junior faculty, postdocs, and senior graduate students) in mathematical biology and to encourage interactions with other
activities include plenary talks and poster sessions, as well as group
discussions on issues relevant to mathematical biologists. Several
abstracts will be chosen
for short talks as well as poster presentations.
Limited funding is available on a competitive basis.
cordially invite young mathematical biologists to participate. For full
consideration, please apply by May 1, 2013. To apply, click this link

Plenary Speakers

Lisa Fauci, Tulane University

Kresimir Josic, University of Houston

Claudia Neuhauser, University of Minnesota

Sebastian Schreiber, UC Davis

Arthur Sherman, Laboratory of Biological Modeling, NIDDK, NIH

John Tyson, Virginia Tech

Lani Wu, Southwestern University

Thoughts on an extremely ancient root of the human Y tree

I was recently interviewed by Alan Boyle at NBC to comment on:

An African American Paternal Lineage Adds an Extremely Ancient Root to the Human Y Chromosome Phylogenetic Tree

Fernando L. Mendez, Thomas Krahn, Bonnie Schrack, Astrid-Maria Krahn, Krishna R. Veeramah, August E. Woerner, Forka Leypey Mathew Fomine, Neil Bradman, Mark G. Thomas, Tatiana M. Karafet and Michael F. Hammer

The American Journal of Human Genetics, 28 February 2013

I do think the paper is very exciting. The identification of a new Y lineage is always interesting, and this one appears to be very long-lived. However, after a more careful reading, and some thought, I am not sure I agree with the way the TMRCA (Time to the Most Recent Common Ancestor) of the Y chromosomes was computed. And the ancient TMRCA depends quite a bit on the TMRCA. I have written up my thoughts and submitted them to the American Journal of Human Genetics, AJHG. The AJHG has a pretty strict pre-print policy (emphasis is mine):

“Work intended for submission to AJHG, currently under consideration at AJHG, or in press at AJHG may not be discussed with the media before publication. Providing preprints, granting interviews, discussing data with members of the media, or participating in press conferences in advance of publication without prior approval from the AJHG editorial office may be grounds for rejection.

But, I have gotten permission from the editor to discuss my thoughts about the submitted manuscript with colleagues (and in blog form). I am sharing the full AJHG manuscript with Mendez, but want to summarize here:

Mendez et al. identify a Y chromosome haplotype that has not been characterized before and, with more work, they determine that it is nearly identical to a small group of Y chromosomes from Cameroon. They also estimate the TMRCA for the Y haplotype phylogeny, including this new Y chromosome and find it to be at least twice as large as anyone else, and as noted by the authors themselves, this TMRCA is inconsistent with what is known in the human fossil record.  While the new Y haplotype does increase the diversity, and thus the TMRCA, the TMRCA calculation is extremely sensitive to the mutation rate used. Mendez et al. advocate for using a mutation rate from human pedigree data instead of from comparative genomics. They then derive a mutation for the human Y chromosome from the mutation rate estimated from autosomal pedigree data. The equation they use assumes a linear correlation between the mutation rate on the autosomes, and the mutation rate on the Y chromosome.

I present a case in my response that: 1) it is not appropriate to assume a linear correlation between the mutation rate on the autosomes and the mutation rate on the Y chromosome; 2) the mutation rate Mendez et al. computed for the Y from autosomal data is an order of magnitude lower than the mutation rate that was measured for the Y chromosome from a pedigree analysis in 2009; 3) the resulting TMRCA is inconsistent with what is known about diversity on the mtDNA, autosomes and X chromosome. Further, our own research suggests that selection is acting to reduce diversity on the Y chromosome relative to the autosomes, X, and mtDNA, which would make an extremely high TMRCA on the Y even more incompatible with observed data.

As such, I am curious why the mutation rate measured from Y chromosomes in a pedigree analysis was not used. I think the results would still be quite exciting and novel. Given what we expect to be strong purifying selection acting to reduce diversity on the Y, the same arguments, of ancient population structure  or even archaic introgression may still apply to this unique Y haplotype.

Cross-posted at my blog.

Natural selection reduced diversity on human Y chromosomes

Melissa A. Wilson Sayres, Kirk E. Lohmueller, and Rasmus Nielsen

The human Y chromosome exhibits surprisingly low levels of genetic diversity. This could result from neutral processes if the effective population size of males is reduced relative to females due to a higher variance in the number of offspring from males than from females. Alternatively, selection acting on new mutations, and affecting linked neutral sites, could reduce variability on the Y chromosome. Here, using genome-wide analyses of X, Y, autosomal and mitochondrial DNA, in combination with extensive population genetic simulations, we show that low observed Y chromosome variability is not consistent with a purely neutral model. Instead, we show that models of purifying selection are consistent with observed Y diversity. Further, the number of sites estimated to be under purifying selection greatly exceeds the number of Y-linked coding sites, suggesting the importance of the highly repetitive ampliconic regions. Because the functional significance of the ampliconic regions is poorly understood, our findings should motivate future research in this area.

We have submitted to PLoS Genetics, and I plan to present (as a talk or a poster) at SMBE 2013.

Cross-posted from my website.

Teaching evolution: what should the focus be

This is a repost from here.

Last week I went with a group of postdocs and grad students to teach a lesson on Phylogenetics to local high school freshman. I had the foresight to do a pre-assessment and post-assessment (those results will be coming soon), but I wanted to start by sharing how this experience made me think about how we introduce the concept of evolution.

During one of the breaks, I spoke with the students’ teacher. I told him how, to me, one of the neatest things about studying evolution is understanding the tremendous effects of genetic drift. It amazes me that so much of the natural variation we observe within and across species is due simply to stochastic processes in the population. Selection doesn’t need to enter the picture. It does, of course, most popularly through positive selection acting to increase the frequency of beneficial alleles, and also (and perhaps more often) through purifying selection acting to remove deleterious alleles, or through balancing selection to maintain a balance of alleles that might be harmful under some conditions and helpful under others. And, all of this natural selection can affect the frequency of linked neutral alleles.

But, a large proportion of natural variation doesn’t result from natural selection. It can just accumulate and drift to high frequency or fixation through neutral processes. This could be as populations separate geographically from each other, or if one population experiences a severe reduction in size, or any number of scenarios that change the history of the population. How cool is that?!

Later the teacher went through their evolution lesson. I am, first of all, very excited that they have a whole unit on evolution. They spend several classes introducing the concept of natural selection, giving examples of different island populations of lizards adapting to their new environments, and learn to build phylogenetic trees using the physical features of the lizards, and then analyze DNA sequences from the lizards. Cool!

But, the whole lesson focused on the small part of evolution that is positive natural selection. Sure, positive selection is the cool kid on the block, but I think it would be very instructive, and perhaps even more convincing to also introduce purifying selection (because, hey, there are a lot of sequence/functions/features conserved across any chosen clade), and the awesomeness that is neutral evolution (because otherwise we’re training students to look for zebras see function everywhere they look).

I guess I shouldn’t be surprised by this when, at the NESCent Catalysis meeting today, very qualified evolutionary biologists suggested that one of the primary topics journalists should know about science is natural selection, and then gave a detailed example of positive selection acting on a population.

Maybe natural selection is a good place to start to introduce evolution. It is tangible, easy to understand, and, there are very accessible examples of positive selection. But, there is so much more to evolution that positive selection. I hope educators can see the importance of reaching beyond positive selection.

Tweet tweet: Reporting Across the Culture Wars

I’m live tweeting (@mwilsonsayreS) today through Sunday from NESCent:

Reporting Across the Culture Wars: http://www.nescent.org/cal/calendar_detail.php?id=935

hashtag: #evocomm