A new test for genotype-fitness associations reveals a single microsatellite allele that strongly predicts the nature of tuberculosis infections in wild boar.
Journal - Molecular ecology resources (England )
There is increasing interest in the basis of commonly observed heterozygosity-fitness correlations (HFCs). Two models appear possible, a genome-wide effect due to inbreeding depression, and a single-locus effect due to chance linkage to a gene(s) experiencing balancing selection. Recent studies suggest that the latter tends to be more important in the majority of studies, but tests for the presence of single-locus effects tend to be rather weak. One of the problems is that the linkage disequilibrium between a microsatellite and a nearby gene experiencing balancing selection is never likely to be 100%. With this in mind, we conduct stochastic simulations aimed at determining the conditions under which single-locus HFCs may develop. We also suggest a new approach that could offer improved detection of HFCs but which also offers a more general method for detecting genotype-fitness correlations. Our method is based on looking for the maximum possible strength of association between genotype and fitness, and then asking whether randomized data sets are able to generate similarly strong associations. This method is tested on both simulated and real data. In both cases, our method generates greater levels of significance than current tests. Applied to previously published data from wild boar affected by tuberculosis, the method uncovers a strong single-allele association that is strongly predictive of whether the disease is localized or spreads throughout the body. We further suggest a simple method for dealing with the problem of population structure, and believe this approach will help to identify genomic regions associated with fitness.© 2009 Blackwell Publishing Ltd.
Mutation Biases and Mutation Rate Variation Around Very Short Human Microsatellites Revealed by Human-Chimpanzee-Orangutan Genomic Sequence Alignments.
Journal - Journal of molecular evolution
I have studied mutation patterns around very short microsatellites, focusing mainly on sequences carrying only two repeat units. By using human-chimpanzee-orangutan alignments, inferences can be made about both the relative rates of mutations and which bases have mutated. I find remarkable non-randomness, with mutation rate depending on a base's position relative to the microsatellite, the identity of the base itself and the motif in the microsatellite. Comparing the patterns around (AC)(2) with those around other four-base combinations reveals that (AC)(2) does not stand out as being special in the sense that non-repetitive tetramers also generate strong mutation biases. However, comparing (AC)(2) and (AC)(3) with (AC)(4) reveals a step change in both the rate and nature of mutations occurring, suggesting a transition state, (AC)(4) exhibiting an alternating high-low mutation rate pattern consistent with the sequence patterning seen around longer microsatellites. Surprisingly, most changes in repeat number occur through base substitutions rather than slippage, and the relative probability of gaining versus losing a repeat in this way varies greatly with repeat number. Slippage mutations reveal rather similar patterns of mutability compared with point mutations, being rare at two repeats where most cause the loss of a repeat, with both mutation rate and the proportion of expansion mutations increasing up to 6-8 repeats. Inferences about longer repeat tracts are hampered by uncertainties about the proportion of multi-species alignments that fail due to multi-repeat mutations and other rearrangements.
Candidate genes versus genome-wide associations: which are better for detecting genetic susceptibility to infectious disease?
Journal - Proceedings. Biological sciences / The Royal Society
Technological developments allow increasing numbers of markers to be deployed in case-control studies searching for genetic factors that influence disease susceptibility. However, with vast numbers of markers, true 'hits' may become lost in a sea of false positives. This problem may be particularly acute for infectious diseases, where the control group may contain unexposed individuals with susceptible genotypes. To explore this effect, we used a series of stochastic simulations to model a scenario based loosely on bovine tuberculosis. We find that a candidate gene approach tends to have greater statistical power than studies that use large numbers of single nucleotide polymorphisms (SNPs) in genome-wide association tests, almost regardless of the number of SNPs deployed. Both approaches struggle to detect genetic effects when these are either weak or if an appreciable proportion of individuals are unexposed to the disease when modest sample sizes (250 each of cases and controls) are used, but these issues are largely mitigated if sample sizes can be increased to 2000 or more of each class. We conclude that the power of any genotype-phenotype association test will be improved if the sampling strategy takes account of exposure heterogeneity, though this is not necessarily easy to do.
Using human demographic history to infer natural selection reveals contrasting patterns on different families of immune genes.
Journal - Proceedings. Biological sciences / The Royal Society
Detecting regions of the human genome that are, or have been, influenced by natural selection remains an important goal for geneticists. Many methods are used to infer selection, but there is a general reliance on an accurate understanding of how mutation and recombination events are distributed, and the well-known link between these processes and their evolutionary transience introduces uncertainty into inferences. Here, we present and apply two new, independent approaches; one based on single nucleotide polymorphisms (SNPs) that exploits geographical patterns in how humans lost variability as we colonized the world, the other based on the relationship between microsatellite repeat number and heterozygosity. We show that the two methods give concordant results. Of these, the SNP-based method is both widely applicable and detects selection over a well-defined time interval, the last 50 000 years. Analysis of all human genes by their Gene Ontology codes reveals how accelerated and decelerated loss of variability are both preferentially associated with immune genes. Applied to 168 immune genes used as the focus of a previous study, we show that members of the same gene family tend to yield similar indices of selection, even when located on different chromosomes. We hope our approach will provide a useful tool with which to infer where selection has acted to shape the human genome.
Population-Specific Links Between Heterozygosity and the Rate Human Microsatellite Evolution.
Journal - Journal of molecular evolution
Microsatellites form an abundant class of DNA sequences used widely as genetic markers. Surprisingly, the length of human microsatellites varies highly predictably with distance from Africa, apparently following the linear decline in variability that arose as we colonised the world. Such patterns have been used to argue that heterozygosity modulates the rate of microsatellite evolution. Here I test the ensuing prediction that variation in demographic history will cause individual populations predictably either to lead or to lag any given trend in length. I find that they do: larger populations with locally higher heterozygosity have microsatellites that are longer when a locus is expanding and shorter when a locus is contracting. These patterns remain even after controlling for the stepwise way in which heterozygosity and allele lengths decline across the world. This analysis provides support for a strongly discontinuous model for how human genetic variability is distributed and shows how individual populations differ in the average rate their microsatellites are evolving. Such patterns have the potential to provide a new window onto historical demography.
Heterozygosity increases microsatellite mutation rate, linking it to demographic history.
Journal - BMC genetics (England )
BACKGROUND: Biochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity. RESULTS: We find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations. CONCLUSION: Our results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.
|ISSN : ||1471-2156|
|Mesh Heading : ||Demography Genetics, Population Genotype Humans Microsatellite Repeats Pedigree|
|Mesh Heading Relevant : ||Heterozygote Mutation genetics|
Sexual selection does not influence minisatellite mutation rate.
Journal - BMC evolutionary biology (England )
BACKGROUND: Moller and Cuervo report a significant trend between minisatellite mutation rate and the frequency of extra-pair copulations in birds. This is interpreted as evidence that the high rate of evolution demanded by sexual selection has itself selected for a higher mutation rate in species where selection is strongest. However, there are good a priori reasons for believing that their method of calculating minisatellite mutation rates will be highly error prone and a poor surrogate measure of the evolutionary rate of genes. I therefore attempted to replicate their results using both their data and an independent data set based on papers they failed to locate. RESULTS: I find that Moller and Cuervo's data set contains numerous errors that act somewhat to strengthen their key regression. More importantly, data from uncited papers fail to replicate their reported trend and one species in particular, Vireo olivaceus, is apparently deliberately omitted, yet its inclusion removes significance from the original correlation. Over the small number of cases were comparisons can be made, mutation rate estimates do not differ between species but do vary significantly depending on the laboratory/operator. CONCLUSION: There appears to be no clear relationship between minisatellite mutation rate and EPC rate in birds. The previously reported trend can be attributed to data transcription errors and unfortunate data selection. My analysis highlights the importance of total methodological transparency when conducting meta-analyses.
|ISSN : ||1471-2148|
|Mesh Heading : ||Animals Birds Evolution, Molecular Genetic Variation Minisatellite Repeats Phylogeny|
|Mesh Heading Relevant : ||Mutation Sexual Behavior, Animal genetics genetics|
Evidence that two main bottleneck events shaped modern human genetic diversity.
Journal - Proceedings. Biological sciences / The Royal Society
There is a strong consensus that modern humans originated in Africa and moved out to colonize the world approximately 50 000 years ago. During the process of expansion, variability was lost, creating a linear gradient of decreasing diversity with increasing distance from Africa. However, the exact way in which this loss occurred remains somewhat unclear: did it involve one, a few or a continuous series of population bottlenecks? We addressed this by analysing a large published dataset of 783 microsatellite loci genotyped in 53 worldwide populations, using the program 'Bottleneck'. Immediately following a sharp population decline, rare alleles are lost faster than heterozygosity, creating a transient excess of heterozygosity relative to allele number, a feature that is used by Bottleneck to infer historical events. We find evidence of two primary events, one 'out of Africa' and one placed around the Bering Strait, where an ancient land bridge allowed passage into the Americas. These findings agree well with the regions of the world where the largest founder events might have been expected, but contrast with the apparently smooth gradient of variability that is revealed when current heterozygosity is plotted against distance from Africa.
Heterozygosity and mutation rate: evidence for an interaction and its implications: the potential for meiotic gene conversions to influence both mutation rate and distribution.
Journal - BioEssays : news and reviews in molecular, cellular and developmental biology
If natural selection chose where new mutations occur it might well favour placing them near existing polymorphisms, thereby avoiding disruption of areas that work while adding novelty to regions where variation is tolerated or even beneficial. Such a system could operate if heterozygous sites are recognised and 'repaired' during the initial stages of crossing over. Such repairs involve an extra round of DNA replication, providing an opportunity for further mutations, thereby raising the local mutation rate. If so, the changes in heterozygosity that occur when populations grow or shrink could feed back to modulate both the rate and the distribution of mutations. Here, I review evidence from isozymes, microsatellites and single nucleotide polymorphisms that this potential is realised in real populations. I then consider the likely implications, focusing particularly on how these processes might affect microsatellites, concluding that heterozygosity does impact on the rate and distribution of mutations.
Body temperature predicts maximum microsatellite length in mammals.
Journal - Biology letters (England )
A long-standing mystery in genome evolution is why short tandem repeats vary so much in length and frequency. Here, we test the hypothesis that body temperature acts to influence the rate and nature of slippage-based mutations. Using the data from both 28 species where genome sequencing is advanced and 76 species from which marker loci have been published, we show that in mammals, maximum repeat number is inversely correlated with body temperature, with warmer-blooded species having shorter 'long' microsatellites. Our results support a model of microsatellite evolution in which maximum length is limited by a temperature-dependent stability threshold.
|ISSN : ||1744-9561|
|Mesh Heading : ||Animals Body Temperature Cloning, Molecular Genome Mammals Models, Genetic|
|Mesh Heading Relevant : ||Evolution, Molecular Microsatellite Repeats genetics genetics|
Mix and match - hybridization reveals hidden complexity in seal breeding behaviour.
Journal - Molecular ecology (England )
Not so long ago, mammalian breeding systems were seen as dominated by males fighting each other for the right to mate with passive females. Genetic parentage analysis has been instrumental in changing this view and exposing the key role of female choice. Some of the most interesting discoveries have emerged from work on seals, where extreme polygyny is common but females often seem to have a bigger say than was previously thought. A remarkable case in question involves Macquarie Island, where three species of fur seal recently formed a mixed breeding colony (Goldsworthy et al. 1999). Here, the true colours of both sexes lie unusually exposed, because classical models predict that males of the biggest species will dominate the beach and force females of smaller species to conceive mainly hybrid pups. In a fascinating paper in this issue of Molecular Ecology, Lancaster and colleagues (Lancaster et al. 2007) show that females are not this naïve. Although happy to gain protection for most of the season by sitting in the territory of one of the largest males, regardless of whether he is the same species, females almost always conceive to one of their own kind. The females do this, not because any hybrid male offspring they conceive will be sickly and fail to hold good territories, but because females who pup in their hybrid son's territories will be disproportionately likely to mate elsewhere. Hybrid males seem physically fit but sexually unattractive!
|ISSN : ||0962-1083|
|Mesh Heading : ||Animals Female Fur Seals Male genetics|
|Mesh Heading Relevant : ||Hybridization, Genetic Mating Preference, Animal physiology|
Global genetic positioning: evidence for early human population centers in coastal habitats.
Journal - Proceedings of the National Academy of Sciences of the United States of America (United States )
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.
|ISSN : ||0027-8424|
|Mesh Heading : ||Africa South of the Sahara Central America Demography Humans Middle East|
|Mesh Heading Relevant : ||Genetics, Population Models, Genetic|
Directional evolution of size coupled with ascertainment bias for variation in Drosophila microsatellites.
Journal - Molecular biology and evolution (United States )
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.
|ISSN : ||0737-4038|
|Mesh Heading : ||Animals Drosophila Models, Statistical Polymerase Chain Reaction Species Specificity|
|Mesh Heading Relevant : ||Evolution, Molecular Genetic Variation Microsatellite Repeats Models, Genetic genetics|
The influence of parental relatedness on reproductive success.
Journal - Proceedings. Biological sciences / The Royal Society (England )
The relationship between fitness and parental similarity has been dominated by studies of how inbreeding depression lowers fecundity in incestuous matings. A widespread implicit assumption is that adult fitness (reproduction) of individuals born to parents who are not unusually closely related is more or less equal. Examination of three long-lived vertebrates, the long-finned pilot whale, the grey seal and the wandering albatross reveals significant negative relationships between parental similarity and genetic estimates of reproductive success. This effect could, in principle, be driven by a small number of low quality, inbred individuals. However, when the data are partitioned into individuals with above average and below average parental similarity, we find no evidence that the slopes differ, suggesting that the effect is more or less similar across the full range of parental similarity values. Our results thus uncover a selective pressure that favours not only inbreeding avoidance, but also the selection of maximally dissimilar mates.
|ISSN : ||0962-8452|
|Mesh Heading : ||Animals Birds Dolphins Female Genotype Inbreeding Male Seals, Earless genetics genetics genetics|
|Mesh Heading Relevant : ||Reproduction physiology physiology physiology|
When does conservation genetics matter?
Journal - Heredity (England )
Is this short review we explore the genetic threats facing declining populations, focusing in particular on empirical studies and the emerging questions they raise. At face value, the two primary threats are slow erosion of genetic variability by drift and short-term lowering of fitness owing to inbreeding depression, of which the latter appears the more potent force. However, the picture is not this simple. Populations that have passed through a severe bottleneck can show a markedly reduced ability to respond to change, particularly in the face of novel challenges. At the same time, several recent studies reveal subtle ways in which species are able to retain more useful genetic variability than they 'should', for example by enhanced reproductive success among the most outbred individuals in a population. Such findings call into question the validity of simple models based on random mating, and emphasize the need for more empirical data aimed at elucidating precisely what happens in natural populations.
|ISSN : ||0018-067X|
|Mesh Heading : ||Adaptation, Biological Animals Evolution Genetics, Population Genotype Inbreeding Mutation Selection (Genetics)|
|Mesh Heading Relevant : ||Genetic Variation genetics genetics|
Factors affecting levels of genetic diversity in natural populations.
Journal - Philosophical transactions of the Royal Society of London. Series B, Biological sciences (ENGLAND )
Genetic variability is the clay of evolution, providing the base material on which adaptation and speciation depend. It is often assumed that most interspecific differences in variability are due primarily to population size effects, with bottlenecked populations carrying less variability than those of stable size. However, we show that population bottlenecks are unlikely to be the only factor, even in classic case studies such as the northern elephant seal and the cheetah, where genetic polymorphism is virtually absent. Instead, we suggest that the low levels of variability observed in endangered populations are more likely to result from a combination of publication biases, which tend to inflate the level of variability which is considered 'normal', and inbreeding effects, which may hasten loss of variability due to drift. To account for species with large population sizes but low variability we advance three hypotheses. First, it is known that certain metapopulation structures can result in effective population sizes far below the census size. Second, there is increasing evidence that heterozygous sites mutate more frequently than equivalent homozygous sites, plausibly because mismatch repair between homologous chromosomes during meiosis provides extra opportunities to mutate. Such a mechanism would undermine the simple relationship between heterozygosity and effective population size. Third, the fact that related species that differ greatly in variability implies that large amounts of variability can be gained or lost rapidly. We argue that such cases are best explained by rapid loss through a genome-wide selective sweep, and suggest a mechanism by which this could come about, based on forced changes to a control gene inducing coevolution in the genes it controls. Our model, based on meiotic drive in mammals, but easily extended to other systems, would tend to facilitate population isolation by generating molecular incompatabilities. Circumstances can even be envisioned in which the process could provide intrinsic impetus to speciation.
|ISSN : ||0962-8436|
|Mesh Heading : ||Animals Evolution Female Heterozygote Humans Inbreeding Male Mammals Meiosis Models, Genetic Social Environment Species Specificity Y Chromosome genetics genetics genetics|
|Mesh Heading Relevant : ||Genetic Variation Genetics, Population|
Sexual selection does not influence minisatellite mutation rate
Journal - BMC Evolutionary Biology
BackgroundMoller and Cuervo report a significant trend between minisatellite mutation rate and the frequency of extra-pair copulations in birds. This is interpreted as evidence that the high rate of evolution demanded by sexual selection has itself selected for a higher mutation rate in species where selection is strongest. However, there are good a priori reasons for believing that their method of calculating minisatellite mutation rates will be highly error prone and a poor surrogate measure of the evolutionary rate of genes. I therefore attempted to replicate their results using both their data and an independent data set based on papers they failed to locate.ResultsI find that Moller and Cuervo's data set contains numerous errors that act somewhat to strengthen their key regression. More importantly, data from uncited papers fail to replicate their reported trend and one species in particular, Vireo olivaceus, is apparently deliberately omitted, yet its inclusion removes significance from the original correlation. Over the small number of cases were comparisons can be made, mutation rate estimates do not differ between species but do vary significantly depending on the laboratory/operator.ConclusionThere appears to be no clear relationship between minisatellite mutation rate and EPC rate in birds. The previously reported trend can be attributed to data transcription errors and unfortunate data selection. My analysis highlights the importance of total methodological transparency when conducting meta-analyses.
Homozygosity and risk of childhood death due to invasive bacterial disease
Journal - BMC Medical Genetics
BackgroundGenetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers.Methods148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality.ResultsAt five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 – 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19–49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined.ConclusionBalanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.
Heterozygosity increases microsatellite mutation rate, linking it to demographic history
Journal - BMC Genetics
BackgroundBiochemical experiments in yeast suggest a possible mechanism that would cause heterozygous sites to mutate faster than equivalent homozygous sites. If such a process operates, it could undermine a key assumption at the core of population genetic theory, namely that mutation rate and population size are indpendent, because population expansion would increase heterozygosity that in turn would increase mutation rate. Here we test this hypothesis using both direct counting of microsatellite mutations in human pedigrees and an analysis of the relationship between microsatellite length and patterns of demographically-induced variation in heterozygosity.ResultsWe find that microsatellite alleles of any given length are more likely to mutate when their homologue is unusually different in length. Furthermore, microsatellite lengths in human populations do not vary randomly, but instead exhibit highly predictable trends with both distance from Africa, a surrogate measure of genome-wide heterozygosity, and modern population size. This predictability remains even after statistically controlling for non-independence due to shared ancestry among populations.ConclusionOur results reveal patterns that are unexpected under classical population genetic theory, where no mechanism exists capable of linking allele length to extrinsic variables such as geography or population size. However, the predictability of microsatellite length is consistent with heterozygote instability and suggest that this has an important impact on microsatellite evolution. Whether similar processes impact on single nucleotide polymorphisms remains unclear.