Biomedical subjects
Publications and source records attributed to D Charlesworth.
Although much is known about the genetic basis of reproductive isolation between species, little is understood about its underlying evolutionary causes. A study of two very closely related, but reproductively isolated, plant species has provided some valuable insights.
Simulations are used to investigate the expected pattern of variation at loci under different forms of multi-allelic balancing selection in a finite island model of a subdivided population. The objective is to evaluate the effect of restricted migration among demes on the distribution of polymorphism at the selected loci at equilibrium, and to compare the results with those expected for a neutral locus. The results show that the expected number of alleles maintained, and numbers of nucleotide differences between alleles, are relatively insensitive to the migration rate, and differentiation remains low even under very restricted migration. However, nucleotide divergence between copies of functionally identical alleles increases sharply when migration decreases. These results are discussed in relation to published surveys of allelic diversity in MHC and plant self-incompatibility systems, and to the possibility of inferring ancient population genetic events and processes. In addition, it is shown that, for sporophytic self-incompatibility systems, it is not necessarily true in a subdivided population that recessive alleles are more frequent than dominant ones.
The effect of multi-allelic balancing selection on nucleotide diversity at linked neutral sites was investigated by simulations of subdivided populations. The motivation is to understand the behaviour of self-recognition systems such as the MHC and plant self-incompatibility. For neutral sites, two types of subdivision are present: (1) into demes (connected by migration), and (2) into classes defined by different functional alleles at the selected locus (connected by recombination). Previous theoretical studies of each type of subdivision separately have shown that each increases diversity, and decreases the relative frequencies of low-frequency variants, at neutral sites or loci. We show here that the two types of subdivision act non-additively when sampling is at the whole population level, and that subdivision produces some non-intuitive results. For instance, in highly subdivided populations, genetic diversity at neutral sites may decrease with tighter linkage to a selected locus or site. Another conclusion is that, if there is population subdivision, balancing selection leads to decreased expected FST values for neutral sites linked to the selected locus. Finally, we show that the ability to detect balancing selection by its effects on linked variation, using tests such as Tajima's D, is reduced when genes in a subdivided population are sampled from the total population, rather than within demes.
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Although all human populations avoid close inbreeding, the effect of inbreeding avoidance on genotype proportions has not been formally considered. This paper examines the expected proportions of genotype frequencies after adjusting the Hardy-Weinberg model for close inbreeding avoidance in an inbred population. This corrected model was used to evaluate genotype distributions for HLA haplotypes and haplotypes created from three microsatellite loci on human chromosome 13 in a sample of 315 married Hutterites. In this sample, there were five individuals who were homozygous for an HLA haplotype and 15 individuals who were homozygous for a chromosome 13 haplotype. The expected numbers of homozygotes were 21 for HLA and 26 for chromosome 13 haplotypes using a model adjusted for overall inbreeding (P = 0.00031 for HLA and P = 0.019 for chromosome 13) and 18 for HLA and 22 chromosome 13 haplotypes using a model adjusted for both overall inbreeding and close inbreeding avoidance (P = 0. 0016 for HLA and P = 0.099 for chromosome 13). The model that takes into account both overall inbreeding and inbreeding avoidance provided a better fit to the observed genotype distributions for chromosome 13 haplotypes (P = 0.099), suggesting that nonrandom aspects of Hutterite mating structure, other than inbreeding and inbreeding avoidance, have small effects on genotype distributions in the population. The fact that significant deficiencies of HLA homozygotes persist after taking into account inbreeding avoidance further suggests that factors related to the HLA haplotype per se influence the genotype proportions at HLA loci in the Hutterites.
A multilocus stochastic model is developed to simulate the dynamics of mutational load in small populations of various sizes. Old mutations sampled from a large ancestral population at mutation-selection balance and new mutations arising each generation are considered jointly, using biologically plausible lethal and deleterious mutation parameters. The results show that inbreeding depression and the number of lethal equivalents due to partially recessive mutations can be partly purged from the population by inbreeding, and that this purging mainly involves lethals or detrimentals of large effect. However, fitness decreases continuously with inbreeding, due to increased fixation and homozygosity of mildly deleterious mutants, resulting in extinctions of very small populations with low reproductive rates. No optimum inbreeding rate or population size exists for purging with respect to fitness (viability) changes, but there is an optimum inbreeding rate at a given final level of inbreeding for reducing inbreeding depression or the number of lethal equivalents. The interaction between selection against partially recessive mutations and genetic drift in small populations also influences the rate of decay of neutral variation. Weak selection against mutants relative to genetic drift results in apparent overdominance and thus an increase in effective size (Ne) at neutral loci, and strong selection relative to drift leads to a decrease in Ne due to the increased variance in family size. The simulation results and their implications are discussed in the context of biological conservation and tests for purging.
Data on the effects of inbreeding on fitness components are reviewed in the light of population genetic models of the possible genetic causes of inbreeding depression. Deleterious mutations probably play a major role in causing inbreeding depression. Putting together the different kinds of quantitative genetic data, it is difficult to account for the very large effects of inbreeding on fitness in Drosophila and outcrossing plants without a significant contribution from variability maintained by selection. Overdominant effects of alleles on fitness components seem not to be important in most cases. Recessive or partially recessive deleterious effects of alleles, some maintained by mutation pressure and some by balancing selection, thus seem to be the most important source of inbreeding depression. Possible experimental approaches to resolving outstanding questions are discussed.
To test the theoretical prediction that highly inbreeding populations should have low neutral genetic diversity relative to closely related outcrossing populations, we sequenced portions of the cytosolic phosphoglucose isomerase (PgiC) gene in the plant genus Leavenworthia, which includes both self-incompatible and inbreeding taxa. On the basis of sequences of intron 12 of this gene, the expected low diversity was seen in both populations of the selfers Leavenworthia uniflora and L. torulosa and in three highly inbreeding populations of L. crassa, while high diversity was found in self-incompatible L. stylosa, and moderate diversity in L. crassa populations with partial or complete self-incompatibility. In L. stylosa, the nucleotide diversity was strongly structured into three haplotypic classes, differing by several insertion/deletion sequences, with linkage disequilibrium between sequences of the three types in intron 12, but not in the adjacent regions. Differences between the three kinds of haplotypes are larger than between sequences of this gene region from different species. The haplotype divergence suggests the presence of a balanced polymorphism at this locus, possibly predating the split between L. stylosa and its two inbreeding sister taxa, L. uniflora and L. torulosa. It is therefore difficult to distinguish between different potential causes of the much lower sequence diversity at this locus in inbreeding than outcrossing populations. Selective sweeps during the evolution of these populations are possible, or background selection, or merely loss of a balanced polymorphism maintained by overdominance in the populations that evolved high selfing rates.
In Brassica species, self-incompatibility is controlled genetically by haplotypes involving two known genes, SLG and SRK, and possibly an as yet unknown gene controlling pollen incompatibility types. Alleles at the incompatibility loci are maintained by frequency-dependent selection, and diversity at SLG and SRK appears to be very ancient, with high diversity at silent and replacement sites, particularly in certain "hypervariable" portions of the genes. It is important to test whether recombination occurs in these genes before inferences about function of different parts of the genes can be made from patterns of diversity within their sequences. In addition, it has been suggested that, to maintain the relationship between alleles within a given S-haplotype, recombination is suppressed in the S-locus region. The high diversity makes many population genetic measures of recombination inapplicable. We have analyzed linkage disequilibrium within the SLG gene of two Brassica species, using published coding sequences. The results suggest that intragenic recombination has occurred in the evolutionary history of these alleles. This is supported by patterns of synonymous nucleotide diversity within both the SLG and SRK genes, and between domains of the SRK gene. Finally, clusters of linkage disequilibrium within the SLG gene suggest that hypervariable regions are under balancing selection, and are not merely regions of relaxed selective constraint.
A study of DNA polymorphism and divergence was conducted for the cytosolic phosphoglucose isomerase (PGI:E.C.5.3.1.9) gene of five species of the mustard genus Leavenworthia: Leavenworthia stylosa, L. alabamica, L. crassa, L. uniflora, and L. torulosa. Sequences of an internal 2.3-kb PgiC gene region spanning exons 6-16 were obtained from 14 L. stylosa plants from two natural populations and from one to several plants for each of the other species. The level of nucleotide polymorphism in L. stylosa PgiC gene was quite high (pi = 0.051, theta = 0.052). Although recombination is estimated to be high in this locus, extensive haplotype structure was observed for the entire 2.3-kb region. The L. stylosa sequences fall into at least two groups, distinguished by the presence of several indels and nucleotide substitutions, and one of the three charge change nucleotide replacements within the region sequenced correlates with the haplotypes. The differences between the haplotypes are older than between the species, and the haplotypes are still segregating in at least two of five species studied. There is no evidence of recent or ancient population subdivision that could maintain distinct haplotypes. The age of the haplotypes and the results of Kelly's Z(nS) and Wall's B and Q tests with recombination suggest that the haplotypes are maintained due to balancing selection at or near this locus.
Studies at the nucleotide level on the nuclear flower development gene cycloidea (cyc) in seven Antirrhinum, two Misopates, one Linaria, one Cymbalaria, and one Digitalis species revealed that cyc is a member of a gene family composed of at least five apparently functional genes. The estimated ages of the duplication events that created this gene family are from 7.5 Myr to more than 75 Myr. We also report the first estimates of DNA sequence diversity for species of Antirrhinum and Misopates. Low between-species variability suggests that this group of species may have diverged recently.
Selection at linked loci probably reduces the variability of genes in regions of infrequent recombination. Detailed sequence information is needed to test possible causes of this effect; such information is now becoming available, but its interpretation can be difficult.
Most flowering plants are hermaphroditic, having flowers with both male and female parts. Less than 4% of plant species are dioecious (with individuals of separate sexes), and many of these species have chromosome-mediated sex determination. The taxonomic distribution of separate sexes and chromosomal sex-determination systems in the flowering plants indicates that plant sex chromosomes have evolved recently through replicated, independent events, contrasting with the ancient origins of mammalian and insect sex chromosomes. Plant sex chromosomes, therefore, offer opportunities to study the most interesting early stages of the evolution of sex chromosomes. Here we show that a gene encoding a male-specific protein is linked to the X chromosome in the dioecious plant Silene latifolia, and that it has a degenerate homologue in the non-pairing region of the Y chromosome. The Y-linked locus has degenerated as a result of nucleotide deletion and the accumulation of repetitive sequences. We have identified both the first X-linked gene and the first pair of homologous sex-linked loci to be found in plants. The homology between the active X-linked locus and the degenerate Y-linked locus supports a common ancestry for these two loci.
Levels of neutral genetic diversity within and between populations were compared between outcrossing (self-incompatible) and inbreeding populations in the annual plant genus Leavenworthia. Two taxonomically independent comparisons are possible, since self-incompatibility has been lost twice in the group of species studied. Within inbred populations of L.uniflora and L.crassa, no DNA sequence variants were seen among the alleles sampled, but high diversity was seen in alleles from populations of the outcrosser L. stylosa, and in self-incompatible L. crassa populations. Diversity between populations was seen in all species. Although total diversity values were lower in the sets of inbreeding populations, between-population values were as high or higher, than those in the outcrossing taxa. Possible reasons for these diversity patterns are discussed. As the effect of inbreeding appears to be a greater than twofold reduction in diversity, we argue that some process such as selection for advantageous mutations, or against deleterious mutations, or bottlenecks occurring predominantly in the inbreeders, appears necessary to account for the findings. If selection for advantageous mutations is responsible, it appears that it must be some form of local adaptive selection, rather than substitution of alleles that are advantageous throughout the species. This is consistent with the finding of high between-population diversity in the inbreeding taxa.
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Self-incompatibility systems in different angiosperm families are reviewed, and the evidence that incompatibility has arisen several times is outlined. New data on the sequence polymorphism of self-incompatibility loci from two different angiosperm families are compared with results from other highly polymorphic loci, particularly MHC loci. We discuss what molecular genetic analyses of these sequences can tell us about the nature and maintenance of the polymorphism at self-incompatibility loci. We suggest that there is evidence for recombination at the Brassica self-incompatibility loci, so that it may be possible to discern regions that are particularly functionally important in the recognition reaction, even though the long-term maintenance of polymorphisms in these amino acid residues has caused the evolution of many other sequence differences between alleles.
Levels of allozyme diversity were studied in five species of the annual plant genus Leavenworthia. The breeding systems of the populations were also characterized in terms of measures of autogamous seed-set and self-fertility. The populations that appeared more inbreeding by these criteria also tended to have lower within-population gene diversity (Hs) values, but there was nevertheless considerable allozyme variability in two of the four sets of inbred populations studied. Comparing the outcrosser L. stylosa and the related inbreeders L. uniflora and L. torulosa the reduction in diversity associated with inbreeding was very high, as no variants were seen within populations of the inbreeders. In L. crassa and L. alabamica, the reduction was lower, but correcting for the fact that this comparison is over less extreme selfing rate differences, it is estimated that the difference between extreme inbreeding and outcrossing populations of L. crassa considerably exceeds twofold. These results are compared with published studies within closely related taxa with different inbreeding levels. The effect of inbreeding on allozyme diversity is consistently larger than has been estimated from comparisons of unrelated species.