Biomedical subjects
Publications and source records attributed to William Amos.
Robotic systems allow vast genetic data sets to be generated automatically with little manual input, raising questions about accuracy. To test whether errors occur randomly, I used the frequencies of missing genotypes in a large human data set to construct a population tree. Remarkably, the gaps appear to carry as strong a phylogenetic signal as the actual data themselves.
When homologous microsatellites are compared between species, significant differences in mean length are often noted. A dominant cause of these length differences is ascertainment bias due to selection for maximum repeat number and repeat purity when the markers are being developed. However, even after ascertainment bias has been allowed for through reciprocal comparisons, significant length differences remain, suggesting that the average microsatellite mutation rate differs between species. Two classes of mechanism have been proposed: rapid evolution of enzymes involved in the generation and repair of slippage products (enzyme evolution model) and heterozygote instability, whereby interchromosomal events at heterozygous sites offer extra opportunities for mutations to occur (heterozygote instability model). To examine which of these hypotheses is most likely, we compared ascertainment bias and species length differences between humans and chimpanzees in autosomal and Y chromosomal microsatellites. We find that levels of ascertainment bias are indistinguishable, but that interspecies length differences are significantly greater for autosomal loci compared with haploid Y chromosomal loci. Such a pattern is consistent with predictions from the heterozygote instability model and is not expected under models of microsatellite evolution that do not include interchromosomal events such as the enzyme evolution model.
For an alternative perspective on relationships among human populations, we combined genetic and geographic information, using allele frequency gradients to place populations and individuals on the globe. Reanalyzing published data on 51 worldwide populations [Rosenberg, N. A., Pritchard, J. K., Weber, J. L., Cann, H. M., Kidd, K. K., Zhivitovsky, L. A. & Feldman, M. W. (2002) Science 298, 2381-2385] reveals five geographic clusters lying in plausible sites either of early agricultural innovation or on ancient migration routes. Also, the inferred sites show significant association with coastlines, suggesting that most early humans lived near large bodies of water. Our approach is flexible, and developments should prove useful both for exploring historical demography and for the identification of likely origin for unknown forensic samples.
Low genetic heterozygosity is associated with loss of fitness in many natural populations. However, it remains unclear whether the mechanism is related to general (i.e. inbreeding) or local effects, in particular from a subset of loci lying close to genes under balancing selection. Here we analyse involving heterozygosity-fitness correlations on neonatal survival of California sea lions and on susceptibility to hookworm (Uncinaria spp.) infection, the single most important cause of pup mortality. We show that regardless of differences in hookworm burden, homozygosity is a key predictor of hookworm-related lesions, with no single locus contributing disproportionately. Conversely, the subsequent occurrence of anaemia due to blood loss in infected pups is overwhelmingly associated with homozygosity at one particular locus, all other loci showing no pattern. Our results suggest contrasting genetic mechanisms underlying two pathologies related to the same pathogen. First, relatively inbred pups are less able to expel hookworms and prevent their attachment to the intestinal mucosa, possibly due to a weakened immune response. In contrast, infected pups that are homozygous for a gene near to microsatellite Hg4.2 are strongly predisposed to anaemia. As yet, this gene is unknown, but could plausibly be involved in the blood-coagulation cascade. Taken together, these results suggest that pathogenic burden alone may not be the main factor regulating pathogen-related mortality in natural populations. Our study could have important implications for the conservation of small, isolated or threatened populations, particularly when they are at a risk of facing pathogenic challenges.
Recent studies that reveal a correlation between heterozygosity and fitness in natural populations have rekindled interest in whether balancing selection is widespread or an evolutionary oddity. We therefore quantified heterozygote advantage at 12 microsatellite markers in both inbred and outbred crosses of Drosophila grown under different forms of environmental stress. As expected, inbreeding depression reduces fitness relative to the outbred controls. In addition, many loci exhibit heterozygote advantage over and above any effect due to inbreeding, with approximately 30% of markers showing an effect in any given culture condition and approximately 75% of markers showing an effect in at least one of the four culture conditions. To explore the extent of linkage disequilibrium surrounding these loci we further typed four new markers close to each of the three strongest hits. We find a pattern where the extent of heterozygote excess tends to decline to nonsignificance within around 1.5 megabases (Mb) either side of the original hit. Crude extrapolation suggests 12 genes or regions experience detectable levels of heterozygote advantage in any one condition and as many as 25 overall. Thus, balancing selection is widespread and is likely to play an important role in maintaining genetic variability.
Surveys of variability of homologous microsatellite loci among species reveal an ascertainment bias for microsatellite length where microsatellite loci isolated in one species tend to be longer than homologous loci in related species. Here, we take advantage of the availability of aligned human and chimpanzee genome sequences to compare length difference of homologous microsatellites for loci identified in humans to length difference for loci identified in chimpanzees. We are able to quantify ascertainment bias for a range of motifs and microsatellite lengths. Because ascertainment bias should not exist if a microsatellite selected in one species is as likely to be longer as it is to be shorter than its homologue, we propose that the nature of ascertainment bias can provide evidence for understanding how microsatellites evolve. We show that bias is greater for longer microsatellites but also that many long microsatellites have short homologues. These results are consistent with the notion that growth of long microsatellites is constrained by an upper length boundary that, when reached, sometimes results in large deletions. By evaluating ascertainment bias separately for interrupted and uninterrupted repeats we also show that long microsatellites tend to become interrupted, thereby contributing a second component of ascertainment bias. Having accounted for ascertainment bias, in agreement with results published elsewhere, we find that microsatellites in humans are longer on average than those in chimpanzees. This length difference is similar among repeat motifs but surprisingly comprises two roughly equal components, one associated with the repeats themselves and one with the flanking sequences. The differences we find can only be explained if microsatellites are both evolving directionally under a biased mutation process and are doing so at different rates in different closely related species.
A recent observation that female Antarctic fur seals foster pups born to related females raises the fascinating possibility that kin selection may promote altruistic behaviour even on a crowded breeding beach, where individual interactions are frequent and complex. However, the use of genetic markers to identify small numbers of unusually highly related individuals is fraught with difficulty due to the likely presence of genotyping errors and related problems. Consequently, we examined an enlarged dataset where errors had been reduced to an absolute minimum by a combination of close scrutiny and repeat genotyping. We find no support for the idea that females preferentially suckle pups born to female relatives. Instead, the previously reported pattern can be explained by a combination of genotyping errors and de novo mutations. Our study emphasizes the need for caution when interpreting rare events that occur at a rate approaching that expected for normal genotyping errors.
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Bovine tuberculosis (bTB) is an important re-emerging zoonotic disease, causing major economic losses and constraining international trade of animals and their products. Despite eradication programmes, some countries continue to encounter outbreaks, mainly due to wildlife acting as primary hosts or reservoirs. While the genetic component of tuberculosis in humans and cattle is well documented, the role of genetic factors as modulators of bTB resistance remains unclear for natural populations. To address this issue, we investigated the relative contribution of host genetic variability to susceptibility to bTB infection and disease progression in wild boars from southern Spain. We found that genetic heterozygosity is an important predictor of bTB, not only modulating resistance to infection but also influencing containment of disease progression in infected individuals. Our results provide further evidence that host genetic variability plays a central role in natural populations. Testing each marker separately reveals evidence of both general and single-locus associative effects on bTB and several loci reveal high homology to regions of the genome with known immune function. Our results may prove to be crucial for understanding outbreaks of bTB in wildlife that could potentially affect domestic livestock and humans.
Recent studies of non-social animals have shown that sexually selected traits signal at least one measure of genetic quality: heterozygosity. To determine whether similar cues reveal group quality in more complex social systems, we examined the relationship between territory size, song structure and heterozygosity in the subdesert mesite (Monias benschi), a group-living bird endemic to Madagascar. Using nine polymorphic microsatellite loci, we found that heterozygosity predicted both the size of territories and the structure of songs used to defend them: more heterozygous groups had larger territories, and more heterozygous males used longer, lower-pitched trills in their songs. Heterozygosity was linked to territory size and song structure in males, but not in females, implying that these traits are sexually selected by female choice and/or male-male competition. To our knowledge, this study provides the first direct evidence in any animal that territory size is related to genetic diversity. We also found a positive association between seasonal reproductive success and heterozygosity, suggesting that this heritable characteristic is a reliable indicator of group quality and fitness. Given that heterozygosity predicts song structure in males, and can therefore be determined by listening to acoustic cues, we identify a mechanism by which social animals may assess rival groups, prospective partners and group mates, information of potential importance in guiding decisions related to conflict, breeding and dispersal.
Microsatellites are a major component of the human genome, and their evolution has been much studied. However, the evolution of microsatellite flanking sequences has received less attention, with reports of both high and low mutation rates and of a tendency for microsatellites to cluster. From the human genome we generated a database of many thousands of (AC)(n) flanking sequences within which we searched for common characteristics. Sequences flanking microsatellites of similar length show remarkable levels of convergent evolution, indicating shared mutational biases. These biases extend 25-50 bases either side of the microsatellite and may therefore affect more than 30% of the entire genome. To explore the extent and absolute strength of these effects, we quantified the observed convergence. We also compared homologous human and chimpanzee loci to look for evidence of changes in mutation rate around microsatellites. Most models of DNA sequence evolution assume that mutations are independent and occur randomly. Allowances may be made for sites mutating at different rates and for general mutation biases such as the faster rate of transitions over transversions. Our analysis suggests that these models may be inadequate, in that proximity to even very short microsatellites may alter the rate and distribution of mutations that occur. The elevated local mutation rate combined with sequence convergence, both of which we find evidence for, also provide a possible resolution for the apparently contradictory inferences of mutation rates in microsatellite flanking sequences.
We have used a mitochondrial marker to explore the population genetics of an economically important parasite of sheep, Teladorsagia. We examined diversity within and between parasites from three very different host populations, as well as within and between individual hosts. One of our study populations, the Soay sheep on Hirta, St Kilda, is unusually isolated with no sheep having been introduced to the island since 1932. Worm haplotypes from Hirta were compared with those from two other host populations. Remarkably, despite its historical isolation the Hirta population shows similar levels of within-population diversity to the other study populations. No divergence between the three Teladorsagia populations was found, consistent with gene flow between the populations. The high diversity within Teladorsagia populations provides compelling evidence that this variability is a general feature of parasitic nematode populations. Such diversity may be caused by high effective population size, coupled with an increased mutation rate for mtDNA, which has important implications for the spread of anthelmintic resistance in nematode populations.
Recent genetic studies of natural populations have shown that heterozygosity and other genetic estimates of parental relatedness correlate with a wide variety of fitness traits, from juvenile survival and parasite resistance to male reproductive success. Many of these traits involve health and survival, where the underlying mechanism may involve changes in the effectiveness of the immune system. However, for traits such as reproductive success, the likely mechanisms remain less obvious. In this paper, we examine the relationship between heterozygosity and a range of traits that contribute to male reproductive success, including time spent on territories and competitiveness. Our analysis is based on observational and genetic data from eight consecutive breeding seasons at a colony of the Antarctic fur seal, Arctocephalus gazella. Overall, male reproductive success was found to correlate strongly with internal relatedness (IR, a form of heterozygosity). When different components of success were analyzed, we found that IR correlates independently with reproductive longevity, time spent ashore, and competitive ability per unit mating opportunity on the study beach, with more heterozygous males being more successful. Behavioral observations were sufficiently detailed to allow examination of how daily mean IR values for males present on the beach varied within seasons and from year to year. Again, significant variation was found both among and within seasons, with more homozygous males appearing less able to hold territories in poor seasons when pup production is low and, within a season, at both the start of the season and to some extent around the peak of female estrus. Finally, we tested whether the benefits of high heterozygosity are due mainly to a genomewide effect (e.g. inbreeding depression) or to single locus heterosis by asking whether the relationship between IR and male success was robust to the removal of any single locus or to any pair of loci. Since the relationship remained significant in all cases, we favor a multilocus explanation for the effects we report.
Species-specific differences in microsatellite locus length and ascertainment bias have both been proposed to explain differences in microsatellite variability and length usually observed when loci isolated in one species are used to survey variation in a related species. Here we provide a simple algebraic approach to independently estimate the contributions of true species-specific length differences and ascertainment bias. We apply this approach to a reciprocal-isolation microsatellite study and show contributions of both ascertainment bias and a true longer average microsatellite length in Drosophila melanogaster compared with D. simulans.
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Although mammalian mating systems are classically characterized in terms of male competition and polygyny, it is becoming increasingly apparent that alternative male strategies and female choice may play important roles. For example, females who mate with males from a dominant dynasty risk producing inbred offspring. Many pinnipeds are highly polygynous, but in some species alternative male strategies such as aquatic mating appear to be important, even when behavioral observations suggest strong polygyny. Here, we analyze male reproductive success in the Antarctic fur seal Arctocephalus gazella, an otariid described behaviorally as being highly polygynous, by combining a microsatellite paternity analysis spanning seven consecutive breeding seasons with detailed behavioral data on both sexes. Territorial males fathered 59% of 660 pups analyzed from our study colony. Male reproductive skew was considerable, with a quarter of all paternities assigned to just 12 top individuals on a beach where mean annual pup production was 635. Most males were successful for only a single season, but those able to return over successive years enjoyed rapidly increasing success with each additional season of tenure. We found no evidence of alternative male reproductive tactics such as aquatic or sneaky terrestrial mating. However, paternity was strongly influenced by maternal status. Females observed on the beach without a pup were significantly less likely to conceive to a sampled territorial male than equivalent females that did pup. In addition, their pups carried combinations of paternal alleles that were less likely to be found on the study beach and exhibited lower levels of shared paternity. Thus, from a territorial male's perspective, not all females offer equal opportunities for fertilization.
The colonization of a new habitat is a fundamental process in metapopulation biology, but it is difficult to study. The emigration of colonists from established populations might be induced by resource competition owing to high local population density. Migration distances are also important because they determine the frequency and scale of recolonization and hence the spatial scale of the metapopulation. Traditionally, these factors have been investigated with demographic approaches that are labour-intensive and are only possible in amenable species. In many cases, genetic differentiation is minimal, preventing traditional genetic approaches from identifying the source of colonists unambiguously. Here we present a bayesian approach that integrates genetic, demographic and geographic distance data. We apply the method to study the British metapopulation of grey seals, which has been growing at 6% per year over the last few decades. Our method reveals differential recruitment to three newly founded colonies and implicates density-dependent dispersal in metapopulation dynamics by using genetic data.
Although largely solitary, humpback whales exhibit a number of behaviours where individuals co-operate with one another, for example during bubble net feeding. Such cases could be due to reciprocal altruism brought on by exceptional circumstances, for example the presence of abundant shoaling fish. An alternative explanation is that these behaviours have evolved through kin selection. With little restriction to either communication or movement, diffuse groups of relatives could maintain some form of social organization without the need to travel in tight-nit units. To try to distinguish between these hypotheses, we took advantage of the fact that migrating humpback whales often swim together in small groups. If kin selection is important in humpback whale biology, these groups should be enriched for relatives. Consequently, we analysed biopsy samples from 57 groups of humpback whales migrating off Eastern Australia in 1992. A total of 142 whales were screened for eight microsatellite markers. Mitochondrial DNA sequences (371 bp) were also used to verify and assist kinship identification. Our data add support to the notion that mothers travel with their offspring for the first year of the calf's life. However, beyond the presence of mother-calf/yearling pairs, no obvious relatedness pattern was found among whales sampled either in the same pod or on the same day. Levels of relatedness did not vary between migratory phases (towards or away from the breeding ground), nor between the two sexes considered either overall or in the north or south migrations separately. These findings suggest that, if any social organization does exist, it is formed transiently when needed rather than being a constant feature of the population, and hence is more likely based on reciprocal altruism than kin selection.