Molecular genetics of speciation and human origins.

Abstract

The major histocompatibility complex (MHC) plays a cardinal role in the defense of vertebrates against parasites and other pathogens. In some genes there are extensive and ancient polymorphisms that have passed from ancestral to descendant species and are shared among contemporary species. The polymorphism at the DRBI locus, represented by 58 known alleles in humans, has existed for at least 30 million years and is shared by humans, apes, and other primates. The coalescence theory of population genetics leads to the conclusion that the DRBI polymorphism requires that the population ancestral to modern humans has maintained a mean effective size of 100,000 individuals over the 30-millionyear persistence of this polymorphism. We explore the possibility of occasional population bottlenecks and conclude that the ancestral population could not have at any time consisted of fewer than several thousand individuals. The MHC polymorphisms exclude the theory claiming, on the basis of mitochondrial DNA polymorphisms, that a constriction down to one or few women occurred in Africa, at the transition from archaic to anatomically modern hans, some 200,000 years ago. The data are consistent with, but do not provide specific support for, the claim that human populations throughout the World were at that time replaced by populations migrating from Africa. The MHC and other molecular polymorphisms are consistent with a "muIlIregionalI theory of Pleistocene human evolution that proposes regional continuity of human populations since the time of migrations of Homo erectus to the present, with distinctive regional selective pressures and occasional migrations between populations.

Increased heterozygosity for MHC class II lineages in newborn males

“…The phylogenetic studies of HLA-DRB1 alleles showed that all present day alleles coalesce into two groups about 25-30 million years ago. 31,32 One group consists of all HLA-DRB1 alleles of the HLA-DRB3 (DR52) family and the other one includes the HLA-DRB4 (DR53) and DRB5 (DR51) families. This is in agreement with an earlier study which identified the HLA-DR52 and -DR53 families as evolutionarily most distinct.…”

“…An overdominant selection model involving one heterozygous and two homozygous genotypes for the DRB3 and DRB5 haplotypes yielded a P value of 0.03, and a P value of 0.16 for the DRB4 and DRB5 haplotypes. The lack of a striking selection for HLA-DRB4/DRB5 was interesting in that the HLA-DRB1 alleles of these families have more closely related sequences 31,32 (see Discussion). The presence of evidence for selection of DRB3/DRB4 and DRB3/DRB5 but not for DRB4/DRB5 suggested that even among the supertypical haplotypes only heterozygosity for the most distinct ones selected strongly enough to be detected in a sample of this size.…”

Differential allelic expression of SOS1 and hyperexpression of the activating SOS1 c.755C variant in a Noonan syndrome family

“…We searched for the heterozygosity of SNPs located in regulatory regions, mainly in the promoter and in proximity to the validated miR-124 binding site in the 3′UTR, 19 but we did not detect this condition in the NS family members. It has been estimated that in over 40% of all genes individual in human population at functional cis-regulatory sites is heterozygous 22,23 and DAE affects from 20 to 50% of genes. 18 These functional variants remain difficult to identify as regulatory regions can reside hundreds of thousands of bases away from the transcriptional start site.…”

Distribution of haplotypes from a chromosome 21 region distinguishes multiple prehistoric human migrations

“…However, the number of migrations from Africa is still unknown. A single emergence from Africa has been suggested, judging from haplotypes associated with the CD4 locus on chromosome 12 (6), whereas results from a study of the major-histocompatibility-complex locus imply a more intricate history (13). Recombination and recurrent mutation may impede the reliable inference of intact progenitor haplotypes, causing difficulties in tracing ancestral events.…”