Archive for February, 2010

Natural selection in the modern human population

Friday, February 19th, 2010

Initially posted 10 December 2009 by evomed

Are humans still evolving? In Chapter 6, we reviewed the current debate on the pace and direction of human evolution. It might seem that modern medical technologies and welfare provisions have removed the impact of natural selection on the human population: those who in the past would have died young, today survive into the reproductive period. Yet one problem of this argument is that natural selection works through differential reproductive success rather than differential survival alone. Reproductive technologies and social changes, however, are likely to have an effect. The promise of ‘engineered’ genes in embryos conceived using assisted reproduction technologies is an exciting medical development, yet unlikely to produce evolutionary change, as these directed mutations would probably be swamped by countless mutations emerging naturally in the babies born every year. In contrast, large-scale social developments—such as postponement of pregnancies towards the late reproductive period, artificial restriction of fertility through use of contraception, and sexual selection—are likely to produce an effect. Furthermore ‘traditional’ selective pressures, such as dietary and ecological changes as well as infectious diseases, continue to operate. For instance, a recent study of kuru showed that even a disease that appeared not more than a century ago and persisted in a limited geographic area can produce a sufficient selective pressure to effect an observable genetic change.

Contrary to the suggestions that selection no longer operates, scientists working with large sets of genetic data (3.9-million HapMap SNP dataset) have proposed that the rate of evolution in humans is actually accelerating. This acceleration was proposed to be caused by the larger size and lesser reproductive isolation of the current human population, allowing for a higher probability that a potentially advantageous mutation could occur and persist. But estimating the direction of natural selection in modern societies has been difficult, as scientists lacked sufficiently detailed human data. A recent paper by Byars et al in PNAS capitalized on the rich resource provided by the Framingham Heart Study, an epidemiological study begun in 1948 with the aim of identifying factors contributing to cardiovascular disease, and named after its location, Framingham in Massachusetts, U.S. The aim of the PNAS study was to show that natural selection was operating on contemporary humans and to predict evolutionary changes for some traits with medical significance. While the Framingham Heart Study now follows the third generation, Byars and colleagues took into account only the original and the offspring cohort, as they had completed their reproduction. Furthermore, in contrast to the original study, this one focused on women only. Cultural/behavioural variations (education, smoking, medication) were taken into account as covariates, and secular demographic change was dealt with by dividing women into 6 groups depending on their date of birth, and then measuring their relative reproductive success in comparison to the mean of their cohort. Finally, the variation of a measurement (such as total cholesterol) across longer time span was taken into account by constructing a response surface of each trait for age and time, measuring each individual deviation from the average value, and then calculating a single representative value (the average of the residuals) for each individual.

The traits found to be favoured by natural selection include lower stature, low total cholesterol (yet higher body weight), lower blood pressure, later menopause and earlier beginning of childbearing. The estimated rates of projected evolution are, however, relatively low, and indicate a pace of evolution that is, compared to other animals and accounting for generation time, slow to moderate.

The conclusions of this study go against the previously mentioned predictions of fast evolution, yet it must be remembered that albeit the study was done on a large sample, it was still a limited population, from a relatively restricted geographic area and it comprised no more than two generations. An even larger and longer study would probably produce a more reliable prediction. Furthermore, as the Framingham Heart Study focused on cardiovascular disease, many parameters of potential interest were not measured. For instance, the observed favoured lengthening of the reproductive period is probably based on associated changes in sex hormone levels, so for instance measuring progesterone and estradiol might have resulted in larger observable effects. But all in all, this study provides a valuable piece of information and it is hoped that other large epidemiological and clinical studies in the future would include evolutionary biologists and consequently bring more data into the field.


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The price of lighter skin?

Friday, February 19th, 2010

Initially posted 11 September 2009 by evomed

Chapter 3 introduced the concept of positive selection, which refers to the increase in frequency of specific traits that confer a fitness advantage. Table 3.1 also gave examples of several human genes which have been shown to be under recent positive selection (ie, within the last 10,000 years). It is thought that environmental changes act as strong selective pressures for genotypes that enable adaptation to the new local environment. An example of such a change would be the transition from hunter-gatherer to agricultural practices 10–12,000 years ago. The lactase-coding gene LCT, which enables hydrolysis of the predominant milk sugar lactose, provides an illustrative example. Positive selection for this gene, and hence lactase persistence into adulthood, has been shown in Northern European and East African populations and is attributed to the domestication of cattle and subsequent introduction of milk to the diet.

Several genes involved in skin pigmentation have also shown population-specific selective sweeps, suggesting that the evolution of human skin pigmentation is also driven by adaptation to different climates as humans migrated out of Africa towards more temperate regions. KITLG, which codes for a ligand of the tyrosine kinase receptor encoded by the KIT locus, is one such example. Among other biological properties, the Kit ligand plays a critical role in melanocyte development and migration. KITLG has been shown to be under positive selection in Europeans and East-Asians, but not Africans. Genotyping of an ancestral SNP (rs642742), located at a potentially regulatory region upstream of KITLG, demonstrated that Africans possessed the ancestral A allele while European and East Asian populations displayed a significantly higher frequency of the derived G allele that leads to lighter skin, possibly due to lower KITLG expression than that from the A allele (Miller et al. 2008). The selective pressure for lighter skin is not clear, although vitamin D requirements and sexual selection have been proposed.

Recently, Kanetsky et al. (2009) and Rapley et al. (2009) independently conducted genome-wide association studies (GWAS) to determine markers of testicular germ cell tumors (TGCT). TGCTs are the most commonly diagnosed cancer among young to mid-age males. Genotype frequencies for cases and controls of European ancestry were determined and compared. Seven of the eight SNP markers that reached genome-wide statistical significance (P < 5.0 x 10–8) in the study by Kanetsky et al. were located within the KITLG gene region on 12q22. Independent replication was then performed on two of the SNPs (rs3782179 and rs4474514) in another cohort. Using similar methodology, Rapley et al. found strong evidence of association for two SNPs located on chromosome 12 (rs995030 and rs1508595) which held up after replication. The estimated per-allele odds ratios (OR) for the susceptibility loci on chromosome 12 in the two studies ranged from 2.55 to 3.08—ratios that are remarkably high in comparison to the OR for other GWAS-identified cancer susceptibility loci.

The findings from both teams clearly demonstrate that KITLG is a risk factor for the development of TGCT. It is interesting to note, as have Kanetsky et al., that the incidence of TGCT in men of European ancestry is almost fivefold higher than in black men.  The findings, coupled with HapMap data showing significantly higher disease allele frequency in European than in African ancestry populations, suggest that the difference may be explained at least partially by inherited variation at the KITLG locus. It is important to bear in mind that GWAS can only reveal associations, not causality; however biochemical studies investigating the mechanisms by which lower KITLG expression affects melanocyte properties, and the role that KITLG plays in the development of TGCT, may provide some clues. The similar results from the two TGCT studies suggest that potentially negative consequences of positive selection cannot be overlooked.


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Regulating the age of puberty

Friday, February 19th, 2010

Initially posted 27 July 2009 by evomed

The age of puberty is a central feature of a species’ life history. The mechanism that controls the onset of sexual maturity evolved to allow for successful reproduction. Reproduction is energetically costly for the female and a degree of physical and psychosocial maturity is necessary for successful pregnancy and infant care. In humans, the timing of puberty evolved within ecological conditions that were radically different from ours and in which social independence was achieved at a younger age. Indeed, the gap between the sexual and social maturation continues to increase. Its steady growth is caused not just by the delay of social independence in the modern society but also by the falling age at puberty observed worldwide. It seems that the controls evolved to permit earlier puberty in the conditions of abundance are permanently switched on in our affluent society, where children are taller and heavier than ever before.

Studies published recently in Nature Genetics have begun to reveal some of the biological mechanisms behind the onset of puberty and of its link to the height and weight. A team led by John Perry conducted a meta-analysis of genome-wide association data of 17,520 women from eight different population-based cohorts. The women were all of European descent and had a self-reported age at menarche between 9 and 17 years, with the mean of 13.22 years. The SNPs that passed the significance threshold were all located at either chromosome 6 (6q21) or 9 (9q31.2). The strongest signal at 9q31.2 was observed with SNP rs2090409 (nearest genes TMEM38B, FKTN, FSD1L, TAL2 and ZNF462), where each A allele was associated with a 5-week reduction in menarcheal age. The T allele at rs7759938 within the 6q21 signal was also associated with a 5-week reduction in menarcheal age and it was found near a gene previously associated with a variation in human height, LIN28B. In the same issue of Nature Genetics, Ong at al confirmed the link between LIN28B on chromosome 6 and reduced age at menarche in several cohorts, with each copy of the major C allele at rs314276 reducing the age of menarche by 0.10-0.22 years. The same allele was then found to be associated with earlier breast development, and a higher BMI. In boys, it was found to be linked at age 15 with more advanced pubic hair stage, voice breaking status and tempo of height growth. In both sexes the allele was linked with faster tempo of growth in height between ages 7 and 11.

LIN28B shows high sequence, structural and functional homology with LIN28 on chromosome 1 and both exhibit sequence homology to lin-28 in the much-studied nematode worm Caenorhabditis elegans; deleterious mutations in that gene produce an abnormal tempo of development, while the enhancement of its expression by deletion of regulatory elements delays larval stage expression. It is thus suggested that LIN28B, the first cell marker associated with the timing of puberty, is associated with an evolutionarily old cell regulatory system of human growth and development.

While important, these studies explain only a small part of observed variation: even in homozygotes, the C allele at rs314276 upstream of LIN28B accounts for just a few months of the observed difference. These studies furthermore do not explain the ‘secular trend’ or the widely observed reduced age at puberty in the modern world. It is hoped that the location of other similar cell markers and a closer look into the regulation of their expression, especially during the plastic developmental period, will shed more light on this fundamental life phase.


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We age because we grow

Friday, February 19th, 2010

Initially posted 18 May 2009 by evomed

In Chapter 5 of Principles of Evolutionary Medicine, we discussed the evolutionary biology of aging, and in Chapter 7 we explored the origins of one particular manifestation of aging in humans: the menopause. Among several hypotheses to explain aging, Tom Kirkwood’s idea of the disposable soma proposes that it is energetically less costly (and therefore evolutionarily favoured) to build new organisms from the cells of the germ line (in other words, to reproduce) than to continue to invest in maintaining the soma (the non-reproductive tissues) of the parent organism, particularly if extrinsic mortality (the risk of events such as predation, disease or accident) is high. Somatic tissue will therefore deteriorate from lack of maintenance, leading to senescence and death.

Anthropologist Hillard Kaplan and economist Arthur Robson have extended the disposable soma hypothesis to propose a new mathematical model of aging that explains the main characteristics of human demography. Their model characterises investment in bodily growth – which they call somatic capital – in terms of both quantity (the size of the body) and quality (its functional efficiency). Their model shows that it is evolutionarily optimal to build up quantity (in other words to grow large, which increases economic productivity – the amount of energy an organism can harvest from the environment over its lifetime) but to let the quality of most of the cells in the body deteriorate with time (because a bigger body takes more energy to maintain its quality). If the soma and the germ line are separate, the fidelity of reproduction – quality control of the germ line – can be maintained with little energetic cost because of the tiny number of cells in the germ line relative to the soma. The model also incorporates the idea of intergenerational transfers of capital. A simple example of an intergenerational transfer is lactation, by which energy is transferred from mother to offspring, but more broadly such transfers also include any process by which capital can flow from older to younger individuals – and for humans capital can take many forms, not just energy but also skills and knowledge. The human ability to accumulate knowledge over a lifetime and then to transfer that knowledge to the next generation means that peak economic productivity is shifted to an older age compared with other primates, causing selection for longevity – and, in females in particular, for a period of economically active post-reproductive life.

Predictions from the model fit well with observational studies of human foraging populations, allowing Kaplan and Robinson to conclude that their model explains the biological basis of the following features of human demography:

– mortality initially decreases and then increases with age;

– peak female fertility occurs at approximately the time growth ceases, thereafter declining with age;

– female fertility reaches zero at the menopause, with a substantial period of post-reproductive life;

– humans live longer than other primates.


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