Papers for labmeeting on November 24: genomics and sex ratio evolution

This Wednesday, we will discuss two short papers, one in Nature Genetics and the other one in Nature. They are both very short, but should make interesting reads. The first paper was suggested by Bengt Hansson, and is an example of how the sequencing of entire genomes can shed light over local adaptation, in this case of the plant Arabdopsis lyrata to serpentine soils. You can download that paper here. The second paper is an example of how climatic factors can drive population divergence in sex determination systems, in this case over an altitudinal gradient of an Australian lizard species. You can download that paper here. Abstracts of both papers are provided below.

I hope you enjoy these papers and that we will have a good discussion. Time and place as usual: "Darwin" at 10.15 (Wednesday November 24). Fika volunteers are encouraged to step forward.

Population resequencing reveals local adaptation of Arabidopsis lyrata to serpentine soils  

Thomas L Turner, Elizabeth C Bourne, Eric J Von Wettberg, Tina T Hu & Sergey V Nuzhdin

Nature Genetics 42: 260–263 (2010)

DOI: doi:10.1038/ng.515

A powerful way to map functional genomic variation and reveal the genetic basis of local adaptation is to associate allele frequency across the genome with environmental conditions. Serpentine soils, characterized by high heavy-metal content and low calcium-to-magnesium ratios, are a classic context for studying adaptation of plants to local soil conditions. To investigate whether Arabidopsis lyrata is locally adapted to serpentine soil, and to map the polymorphisms responsible for such adaptation, we pooled DNA from individuals from serpentine and nonserpentine soils and sequenced each 'gene pool' with the Illumina Genome Analyzer. The polymorphisms that are most strongly associated with soil type are enriched at heavy-metal detoxification and calcium and magnesium transport loci, providing numerous candidate mutations for serpentine adaptation. Sequencing of three candidate loci in the European subspecies of A. lyrata indicates parallel differentiation of the same polymorphism at one locus, confirming ecological adaptation, and different polymorphisms at two other loci, which may indicate convergent evolution.

Climate-driven population divergence in sex-determining systems

Ido Pen, Tobias Uller, Barbara Feldmeyer, Anna Harts, Geoffrey M. While & Erik Wapstra

Nature 468: 436–438 (18 November 2010)

DOI: doi:10.1038/nature09512

Sex determination is a fundamental biological process, yet its mechanisms are remarkably diverse. In vertebrates, sex can be determined by inherited genetic factors or by the temperature experienced during embryonic development. However, the evolutionary causes of this diversity remain unknown. Here we show that live-bearing lizards at different climatic extremes of the species’ distribution differ in their sex-determining mechanisms, with temperature-dependent sex determination in lowlands and genotypic sex determination in highlands. A theoretical model parameterized with field data accurately predicts this divergence in sex-determining systems and the consequence thereof for variation in cohort sex ratios among years. Furthermore, we show that divergent natural selection on sex determination across altitudes is caused by climatic effects on lizard life history and variation in the magnitude of between-year temperature fluctuations. Our results establish an adaptive explanation for intra-specific divergence in sex-determining systems driven by phenotypic plasticity and ecological selection, thereby providing a unifying framework for integrating the developmental, ecological and evolutionary basis for variation in vertebrate sex determination.

Relaxed selection and loss of non-beneficial traits

In the latest issue of Trends in Ecology & Evolution, there is a review and metaanalysis of the fascinating phenomen of trait loss after the disappearance of selection pressures maintaining the traits. Classical cases is the loss of vision among cave-dwelling fish or loss of flight ability or antipredator adaptations among birds and insects invading oceanic islands with few predators. This study is briefly reviewed at Science Daily, and one of the co-authors is Andrew P. Hendry, the external opponent of Fabrice Eroukhmanoff's Ph.D.-thesis on November 20 2009.

Fascinating questions to adress here is why do some traits disappear fast, while others take much longer time to decay? According to the results it seems as if two factors might be important in determining the speed by which traits are lost when no longer maintained by selection:

1/Traits that are energetically or nutrient-wise costly are more likely to disappear fast. Examples of such traits are the armour-plate reductions in marine sticklebacks, which disappear fast when these sticklebacks invade freshwater environments, where the minerals that are needed to produce these plates are scarce.

2/Traits that have a relatively simple genetic basis, and which are governed by one or a few loci are lost faster than traits governed by many traits. Examples of such traits include the loss of vision among cave-dwelling animals. Although many genes might influence vision, it might be sufficient with mutations in one or a few genes to cause blindness.

These interesting questions also apply to some of the study systems we are working in our lab, e. g. the Podarcis-lizards that Anna studies on the islets in Greece, where predators are few or the isopods that Fabrice have studied in Lake Krankesjön and Lake Tåkern which have invaded a new limnetic habitat (stonewort), where the isopoods seem to have evolved a suite of different anti-predator adaptations, perhaps as a response to a changed predator regime (invertebrates vs. fish) or perhaps even relaxed overall predation.

More reflections about quantiative genetics from Norway

I am currently in Oslo (Norway) at "Centre for Ecological Synthesis and Evolutinary Synthesis" (CEES) where I have been visiting theoretical evolutionary biologist Thomas F. Hansen. Also visiting here are evolutionary geneticists David Houle and Gunter P. Wagner. So it has been an interesting group of people to discuss, as you understand.

I talked to David Houle about the paradox that the molecular markers explain only a tiny fraction of total genetic variation in human height (see my previous bloggpost), whereas classical quantitative genetic studies (based on covariances between relatives) indicate that the real amount of genetic variation is substantially higher (between 80 and 90 %). David Houle interpreted this discrepancy very much as I did: it provides support for the so-called "infinitisemal model" in quantitative genetics, as formulated (among others) by Russel Lande.

In other words, many loci, perhaps the vast majority of all coding genes, influence human height, but each has a very small contribution in terms of percentages. This is not surprising as many independent genetic factors are likely to influence "condition" or growth, each giving a very small contribution. This makes the prospects for molecular genetic association studies quite bleach, since this approach can only (because of statistical power issues) only detect those few factors that have a relatively large effect. We are left with a situation where quantitative genetic approaches "capture" more of the existing variation than do molecular association studies that fail to detect all these small genetic factors.

This also means that we should perhaps be aware of the fact that many beatiful genetic association studies and studies of candidate genes such as the melanocortin receptor (MC1R) studied by Hopi Hoekstra's laboratory might be untypical and not representative for the vast majority of quantitative traits governed by many different genes (height being one of them). This is not surprising to me, however, it also shows that there is a lot of interesting work remaining to be done and a lot of theoretical and empirical challenges ahead.

Why molecular genetics will not replace quantiative genetics

Today, at our lab-meeting, I briefly mentioned an interesting bloggpost by Juha Merilä at his research group's blogg, that I would like to discuss a bit. The reason is that it is not only interesting from the viewopoint of quantitative genetics vs. molecular genetics per se, but also of its wider implications in terms of the value of reductionism in science vs. emergent properties of biological systems. What do I mean by this?

Emergent properties of systems simply means that "the whole is more than the sum of the parts". This is nothing metaphysical, but it means that one might not fully understand a system simply by de-composing it in to separate parts, because the parts often interact with each other. One actually needs to understand how the parts work together, and it is here where I see the value of quantitative genetics. Quantitative genetics is focussed on the "units" (=traits) that we as evolutionary biologists are most interested in and which we would like to understand how they evolve. It focuses on these higher-level units, while at the same time ignoring the details (=the particular single genes governing the traits). This might be perceived as a weakness of quantiative genetics, but others would argue that it is a strength. I will not dwell in to this here.

Although none of us would deny that the traits are governed by many different genes, as well as the environment of course, we do still not fully understand the genetic basis of the vast majority of traits, in spite of the explosion of molecular information and the presence of fully-sequenced genomes. And if you ask me, I am not sure we will necessarily get the answers to these fundamental questions in biology simply by sequencing even more, or by hoping that new molecular techniques will solve all the remaining questions. In short: the whole will always be more than the sum of the parts, and quantitative genetics is still live and kicking. At least in some circles.

Back to Juha's bloggpost. An interesting "paradox" is that quantitative genetic studies of human height indicate that heritability of height is very high: between 80 and 90 %. In other words, height is a highly heritable trait that can rapidly evolve by natural or sexual selection. One would therefore think that height would be an excellent trait to focus on if we wish to find candidate genes or do genome-wide association studies to identify the precise genes. Such a study has indeed been performed, but as the blogg "Genetic Future" rather brutally points out, these studies have been "a resounding disappointment".

Some more specific examples of these disappointing results:

The first genome-wide association for height, published in September last year, examined 4,921 individuals and found a single significant and replicable variant associated with height (in the HMGA2 gene) that explained a meagre 0.3% of the variation in the general population. The second such scan, published in January this year, examined 6,669 individuals. This study confirmed the HMGA2 finding and identified one further significant signal, this time near the GDF5 and UQCC genes, which again explained less than 0.5% of the total variation. I saw an abstract at the American Society of Human Genetics meeting last year (as yet unpublished, as far as I can tell) in which a genome scan was reported for 10,737 individuals, which pulled out a total of 8 associated variants which together explain just 3% of the variance in height.

To summarise these results: to date genome-wide scans for height, even extremely well-powered ones with more than 10,000 participants, have identified variants responsible for less than 5% of the variation in this trait - despite height being a trait that is largely genetically determined and varies substantially between humans. What's going on?

Well, I certainly do not know the answer, and neither does Juha or the blogger "Genetic Future". But we can safely conclude that a major fraction of the genetic variation in height is "missing" and not picked up in these genome-wide association studies and by the molecular markers. Hopefully, future studies can improve resolution and increase these depressingly low percentages somewhat. However, these low percentages should be somewhat worrying, at least for those who thought that it would be easy to study the molecular basis of this trait. Especially given that we already know that there is ample genetic variation for human height from the quantitative genetic studies.

It seems to me that either the heritability estimates have been severely inflated (e. g. by maternal effects), or the molecular markers do not fully capture all the genetic variation in human height. Although it is definitely possible that heritability is somewhat overestimated, I doubt that heritability will only be a few percent, as the molecular marker studies indicate. Most morphological traits have heritabilities much higher than a few percent, so it seems a safe conclusion that the molecular markers miss a large amount of the genetic variation that is actually present. Therefore, it seems as if the association studies are missing the big picture. The results from these genome-wide association studies must in any case be a big dissappointment, given the large research resources that have been put in to them and the HUGE sample sizes in these studies.

The EGRU-blogg cites a recent update about this work in Nature, and (musingly?) concludes:

"Read the thought provoking ‘news feature’ from Nature by Brend Maher about the statue puzzle. It might even give some (quantum of?) solace for those sticking with their parent-offspring regressions and tedious experiments while the others in their spotless labcoats are drowning in their high throughput data."

Juha Merilä also comments on another interesting bloggpost with the title "Do we still need quantiative genetics in the 21st Century":

"It seems that people were a bit optimistic about the utility of the new technologies in solving old problems. This has also lead to situation where students have jumped into the fancy wagon of genomics, and left quantitative genetics with some interesting (and unfortunate) consequences of which you can read from here:

http://www3.interscience.wiley.com/cgi-bin/fulltext/119408495/HTMLSTART

Actually, all the 2008 volumes of the Journal of Animal Breeding and genetics feature nice Editorials each which touch some general issues interesting also for Evolutionary Biologists. Go and have a look:

http://www3.interscience.wiley.com/journal/118521919/issueyear?year=2008"

I, myself, is like Juha a big fan of quantitative genetics, and I do of course agree with him and his colleagues that this is a useful tool that is unlikely to be replaced by molecular genetics, neither in the short- nor in the long-term. As a matter of fact, molecular genetics might have its greatest utility as a complement to quantitative genetic approaches, e. g. in the combination of QTL-approaches and estimations of quantitative genetic parameters such as to understand the "anatomy" of genetic correlations. Are genetic correlations mainly a result of linkage disequilibrium or pleiotropy, is one such interesting question that can be adressed by the combination of quantitative genetics and QTL-approaches.

And it might of course always be good to keep in mind that one should be critical of scientific bandwagons and premature claims that new techniques will solve all problems. Finally, do not forget the emergent properties and that the whole is always more than the sum of the parts. Reductionism can be taken too far, particularly in biology.