Infectious diseases may have arrested the southward advance of microblades in Upper Palaeolithic East Asia.

An unsolved archaeological puzzle of the East Asian Upper Palaeolithic is why the southward expansion of an innovative lithic technology represented by microblades stalled at the Qinling-Huaihe Line. It has been suggested that the southward migration of foragers with microblades stopped there, which is consistent with ancient DNA studies showing that populations to the north and south of this line had differentiated genetically by 19 000 years ago. Many infectious pathogens are believed to have been associated with hominins since the Palaeolithic, and zoonotic pathogens in particular are prevalent at lower latitudes, which may have produced a disease barrier. We propose a mathematical model to argue that mortality due to infectious diseases may have arrested the wave-of-advance of the technologically advantaged foragers from the north.

Role of error catastrophe in transmission ability of virus.

The role played by error catastrophe is explicitly taken into account in a mathematical formulation to analyze COVID-19 data. The idea is to combine the mathematical genetics formalism of the error catastrophe of mutations in virus gene loci with the standard model of epidemics, which lacks the explicit incorporation of the effect of mutation on the spreading of viruses. We apply this formalism to the case of SARS-CoV-2 virus. We assume the universality of the error catastrophe in the process of analyzing the data. This means that some basic parameter to describe the error catastrophe is independent of which group (country or city) we deal with. Concretely, we analyze Omicron variant data from South Africa and then analyze cases from Japan using the same value of the basic parameter derived in the South Africa analysis. The excellent fit between the two sets of data, one from South Africa and the other from Japan, using the common values of genetic parameters, justifies our assumption of the universality of these parameters.

Lower promoter activity of the ST8SIA2 gene has been favored in evolving human collective brains.

ST8SIA2 is an important molecule regulating expression of the phenotype involved in schizophrenia. Lowered promoter activity of the ST8SIA2 gene is considered to be protective against schizophrenia by conferring tolerance to psychosocial stress. Here, we examined the promoter-type composition of anatomically modern humans (AMHs) and archaic humans (AHs; Neanderthals and Denisovans), and compared the promoter activity at the population level (population promoter activity; PPA) between them. In AMHs, the TCT-type, showing the second lowest promoter activity, was most prevalent in the ancestral population of non-Africans. However, the detection of only the CGT-type from AH samples and recombination tracts in AH sequences showed that the CGT- and TGT-types, exhibiting the two highest promoter activities, were common in AH populations. Furthermore, interspecies gene flow occurred into AMHs from AHs and into Denisovans from Neanderthals, influencing promoter-type compositions independently in both AMHs and AHs. The difference of promoter-type composition makes PPA unique in each population. East and Southeast Asian populations show the lowest PPA. This results from the selective increase of the CGC-type, showing the lowest promoter activity, in these populations. Every non-African population shows significantly lower PPA than African populations, resulting from the TCT-type having the highest prevalence in the ancestral population of non-Africans. In addition, PPA reduction is also found among subpopulations within Africa via a slight increase of the TCT-type. These findings indicate a trend toward lower PPA in the spread of AMHs, interpreted as a continuous adaptation to psychosocial stress arising in migration. This trend is considered as genetic tuning for the evolution of collective brains. The inferred promoter-type composition of AHs differed markedly from that of AMHs, resulting in higher PPA in AHs than in AMHs. This suggests that the trend toward lower PPA is a unique feature in AMH spread.

Two-dimensional site frequency spectrum for detecting, classifying and dating incomplete selective sweeps.

The two-dimensional site frequency spectrum (2D SFS) was investigated to describe the intra-allelic variability (IAV) maintained within a derived allele (D) group that has undergone an incomplete selective sweep against an ancestral allele group. We observed that recombination certainly muddles the ancestral relationships of allelic lineages between the two allele groups; however, the 2D SFS reveals intriguing signatures of recombination as well as the genealogical structure of the D group, particularly the size of a mutation and the time to the most recent common ancestor (TMRCA). Coalescent simulations were performed to achieve powerful and robust 2D SFS-based statistics with special reference to accurate evaluation of IAV, significance of recombination effects, and distinction between hard and soft selective sweeps. These studies were extended to a case wherein an incomplete selective sweep is no longer in progress and ceased in the recent past. The 2D SFS-based method was applied to 100 intronic linkage disequilibrium regions randomly chosen from the East Asian population of modern humans to examine the P value distributions of the summary statistics under the null hypothesis of neutrality in a nonequilibrium demographic model. We argue that about 96% of intronic variants are non-adaptive with a 10% false discovery rate. Furthermore, this method was applied to six genomic regions in Eurasian populations that were claimed to have experienced recent selective sweeps. We found that two of these genomic regions did not have significant signals of selective sweeps, but the remaining four had undergone hard and soft sweeps and were dated, in terms of TMRCA, after the major out-of-Africa dispersal of modern humans.

A new inference method for detecting an ongoing selective sweep.

A simple method was developed to detect signatures of ongoing selective sweeps in single nucleotide polymorphism (SNP) data. Based largely on the traditional site frequency spectrum (SFS), the method additionally incorporates linkage disequilibrium (LD) between pairs of SNP sites and uniquely represents both SFS and LD information as hierarchical "barcodes." This barcode representation allows the identification of a hitchhiking genomic region surrounding a putative target site of positive selection, or a core site. Sweep signals at linked neutral sites are then measured by the proportion (Fc) of derived alleles within the hitchhiking region that are linked in the derived allele group defined at the core site. In measuring Fc or intra-allelic variability in an informative way, certain conditions for derived allele frequencies are required, as illustrated with the human ST8SIA2 locus. Coalescent simulators with and without positive selection are used to assess the false-positive and false-negative rates of the Fc statistic. To demonstrate its power, the method was further applied to the LCT, OCA2, EDAR, SLC24A5 and ASPM loci, which are known to have undergone positive selection in human populations. Overall, the method is powerful and can be used to identify core sites responsible for ongoing selective sweeps.

Positive selection on schizophrenia-associated ST8SIA2 gene in post-glacial Asia.

A number of loci are associated with highly heritable schizophrenia and the prevalence of this mental illness has had considerable negative fitness effects on human populations. Here we focused on one particular schizophrenia-associated gene that encodes a sialyltransferase (ST8SIA2) and is expressed preferentially in the brain with the level being largely determined by three SNPs in the promoter region. It is suggested that the expression level of the ST8SIA2 gene is a genetic determinant of schizophrenia risk, and we found that a geographically differentiated non-risk SNP type (CGC-type) has significantly reduced promoter activity. A newly developed method for detecting ongoing positive selection was applied to the ST8SIA2 genomic region with the identification of an unambiguous sweep signal in a rather restricted region of 18 kb length surrounding the promoter. We also found that while the CGC-type emerged in anatomically modern humans in Africa over 100 thousand years ago, it has increased its frequency in Asia only during the past 20-30 thousand years. These findings support that the positive selection is driven by psychosocial stress due to changing social environments since around the last glacial maximum, and raise a possibility that schizophrenia extensively emerged during the Upper Paleolithic and Neolithic era.

Nonequilibrium Neutral Theory for Hitchhikers.

Selective sweep is a phenomenon of reduced variation at presumably neutrally evolving sites (hitchhikers) in the genome that is caused by the spread of a selected allele at a linked focal site, and is widely used to test for action of positive selection. Nonetheless, selective sweep may also provide an unprecedented opportunity for studying nonequilibrium properties of the neutral variation itself. We have demonstrated this possibility in relation to ancient selective sweep for modern human-specific changes and ongoing selective sweep for local population-specific changes.

Genomic structure and evolution of multigene families: "flowers" on the human genome.

We report the results of an extensive investigation of genomic structures in the human genome, with a particular focus on relatively large repeats (>50 kb) in adjacent chromosomal regions. We named such structures "Flowers" because the pattern observed on dot plots resembles a flower. We detected a total of 291 Flowers in the human genome. They were predominantly located in euchromatic regions. Flowers are gene-rich compared to the average gene density of the genome. Genes involved in systems receiving environmental information, such as immunity and detoxification, were overrepresented in Flowers. Within a Flower, the mean number of duplication units was approximately four. The maximum and minimum identities between homologs in a Flower showed different distributions; the maximum identity was often concentrated to 100% identity, while the minimum identity was evenly distributed in the range of 78% to 100%. Using a gene conversion detection test, we found frequent and/or recent gene conversion events within the tested Flowers. Interestingly, many of those converted regions contained protein-coding genes. Computer simulation studies suggest that one role of such frequent gene conversions is the elongation of the life span of gene families in a Flower by the resurrection of pseudogenes.

Use of Cumulative Poisson Probability Distribution as an Estimator of the Recombination Rate in an Expanding Population: Example of the Macaca fascicularis Major Histocompatibility Complex.

We describe a method to estimate the rate of recombination per generation from the genotypes of a large individual sample of an expanding population, for which the founding event is dated. The approach is illustrated with an application to estimating the major histocompatibility complex (MHC) recombination rate in the Mauritian macaque population. We genotyped 750 macaques by means of 17 microsatellites across the MHC region and reconstructed the seven most frequent haplotypes assumed to represent the founding haplotypes (H(rec(0))) as well as the 31% recombinant haplotypes (H(rec(h))) resulting from a variable number "h" of recombinations between the founding haplotypes. The relative frequencies of the various classes of haplotypes (H(rec(0)) and H(rec(h))) follow a Poisson distribution. By using a maximum likelihood method, we calculated the mean of the Poisson distribution that best fits the data. By dividing this mean by the number of generations (50-100) from the date of the population founding, we deduced that rate of recombination in the MHC is approximately 0.004 to 0.008 in the Mauritian macaque population. When the founding date of the population is precisely known, our method presents a useful alternative to the coalescent method.

Evolutionary origin of peptidoglycan recognition proteins in vertebrate innate immune system.

BACKGROUND: Innate immunity is the ancient defense system of multicellular organisms against microbial infection. The basis of this first line of defense resides in the recognition of unique motifs conserved in microorganisms, and absent in the host. Peptidoglycans, structural components of bacterial cell walls, are recognized by Peptidoglycan Recognition Proteins (PGRPs). PGRPs are present in both vertebrates and invertebrates. Although some evidence for similarities and differences in function and structure between them has been found, their evolutionary history and phylogenetic relationship have remained unclear. Such studies have been severely hampered by the great extent of sequence divergence among vertebrate and invertebrate PGRPs. Here we investigate the birth and death processes of PGRPs to elucidate their origin and diversity. RESULTS: We found that (i) four rounds of gene duplication and a single domain duplication have generated the major variety of present vertebrate PGRPs, while in invertebrates more than ten times the number of duplications are required to explain the repertoire of present PGRPs, and (ii) the death of genes in vertebrates appears to be almost null whereas in invertebrates it is frequent. CONCLUSION: These results suggest that the emergence of new PGRP genes may have an impact on the availability of the repertoire and its function against pathogens. These striking differences in PGRP evolution of vertebrates and invertebrates should reflect the differences in the role of their innate immunity. Insights on the origin of PGRP genes will pave the way to understand the evolution of the interaction between host and pathogens and to lead to the development of new treatments for immune diseases that involve proteins related to the recognition of self and non-self.

Divergence, demography and gene loss along the human lineage.

Genomic DNA sequences are an irreplaceable source for reconstructing the vanished past of living organisms. Based on updated sequence data, this paper summarizes our studies on species divergence time, ancient population size and functional loss of genes in the primate lineage leading to modern humans (Homo sapiens sapiens). The inter- and intraspecific comparisons of DNA sequences suggest that the human lineage experienced a rather severe bottleneck in the Middle Pleistocene, throughout which period the subdivided African population played a predominant role in shaping the genetic architecture of modern humans. Also, published and newly identified human-specific pseudogenes (HSPs) are enumerated in order to infer their significance for human evolution. Of the 121 candidate genes obtained, authentic HSPs turn out to comprise only 25 olfactory receptor genes, four T cell receptor genes and nine other genes. The fixation of HSPs has been too rare over the past 6-7 Myr to account for species differences between humans and chimpanzees.

Frequent gene conversion events between the X and Y homologous chromosomal regions in primates.

BACKGROUND: Mammalian sex-chromosomes originated from a pair of autosomes. A step-wise cessation of recombination is necessary for the proper maintenance of sex-determination and, consequently, generates a four strata structure on the X chromosome. Each stratum shows a specific per-site nucleotide sequence difference (p-distance) between the X and Y chromosomes, depending on the time of recombination arrest. Stratum 4 covers the distal half of the human X chromosome short arm and the p-distance of the stratum is approximately 10%, on average. However, a 100-kb region, which includes KALX and VCX, in the middle of stratum 4 shows a significantly lower p-distance (1-5%), suggesting frequent sequence exchanges or gene conversions between the X and Y chromosomes in humans. To examine the evolutionary mechanism for this low p-distance region, sequences of a corresponding region including KALX/Y from seven species of non-human primates were analyzed. RESULTS: Phylogenetic analysis of this low p-distance region in humans and non-human primate species revealed that gene conversion like events have taken place at least ten times after the divergence of New World monkeys and Catarrhini (i.e., Old World monkeys and hominoids). A KALY-converted KALX allele in white-handed gibbons also suggests a possible recent gene conversion between the X and Y chromosomes. In these primate sequences, the proximal boundary of this low p-distance region is located in a LINE element shared between the X and Y chromosomes, suggesting the involvement of this element in frequent gene conversions. Together with a palindrome on the Y chromosome, a segmental palindrome structure on the X chromosome at the distal boundary near VCX, in humans and chimpanzees, may mediate frequent sequence exchanges between X and Y chromosomes. CONCLUSION: Gene conversion events between the X and Y homologous regions have been suggested, mainly in humans. Here, we found frequent gene conversions in the evolutionary course of primates. An insertion of a LINE element at the proximal end of the region may be a cause for these frequent conversions. This gene conversion in humans may also be one of the genetic causes of Kallmann syndrome.

The origin and genetic variation of domestic chickens with special reference to junglefowls Gallus g. gallus and G. varius.

It is postulated that chickens (Gallus gallus domesticus) became domesticated from wild junglefowls in Southeast Asia nearly 10,000 years ago. Based on 19 individual samples covering various chicken breeds, red junglefowl (G. g. gallus), and green junglefowl (G. varius), we address the origin of domestic chickens, the relative roles of ancestral polymorphisms and introgression, and the effects of artificial selection on the domestic chicken genome. DNA sequences from 30 introns at 25 nuclear loci are determined for both diploid chromosomes from a majority of samples. The phylogenetic analysis shows that the DNA sequences of chickens, red and green junglefowls formed reciprocally monophyletic clusters. The Markov chain Monte Carlo simulation further reveals that domestic chickens diverged from red junglefowl 58,000+/-16,000 years ago, well before the archeological dating of domestication, and that their common ancestor in turn diverged from green junglefowl 3.6 million years ago. Several shared haplotypes nonetheless found between green junglefowl and chickens are attributed to recent unidirectional introgression of chickens into green junglefowl. Shared haplotypes are more frequently found between red junglefowl and chickens, which are attributed to both introgression and ancestral polymorphisms. Within each chicken breed, there is an excess of homozygosity, but there is no significant reduction in the nucleotide diversity. Phenotypic modifications of chicken breeds as a result of artificial selection appear to stem from ancestral polymorphisms at a limited number of genetic loci.

Evolutionary history of sex-linked mammalian amelogenin genes.

Amelogenin (AMEL) arose prior to the emergence of tetrapods and transposed into an intron of the Rho GTPase-activating protein 6 gene. In the mammalian lineage leading to eutherians, a pair of homologous autosomes with this nested gene structure fused with the then already differentiating sex chromosomes by suppressing homologous recombination. As sex-chromosomal differentiation extended to the fused region, a pair of homologous AMEL genes too differentiated from each other in two steps; first in the 5' region (the promoter region to transposon MER5 in intron 2) and second in the remaining 3' region. This resulted in gametologous AMELX and AMELY in the eutherian sex chromosomes. Although the early differentiation of the 5' region between AMELX and AMELY is consistent with the lowered expression level of AMELY, there is no indication for deterioration of AMELY at the amino acid level. Rather, both AMELX and AMELY in particular lineages might undergo positive selection, followed by negative selection to preserve established function. Based on patterns and levels of AMELX and AMELY polymorphisms in the human population, it is also argued that a recombination cold spot near AMELX might be related to the cause of the ancient pseudoautosomal boundary.

Gene flow between species of Lake Victoria haplochromine fishes.

The haplochromine cichlid fishes of Lake Victoria (LV), East Africa, are a textbook example of adaptive radiation-a rapid divergence of multiple morphologically distinguishable forms from a few founding lineages. The forms are generally believed to constitute a "flock" of several hundred reproductively isolated species in a dozen or so genera. This belief has, until now, not been subjected to a test, however. Here, we compare genetic variation at 11 loci in 10 haplochromine populations of 6 different species. Although the genetic diversity in the populations is quite high, using a variety of statistical tests, we find no evidence of genetic differentiation among the populations of LV haplochromines. On genetic distance trees, populations of the same species intermingle with those of different species. At the molecular level, the species are indistinguishable from one another. Genetic comparisons with closely related species in 2 crater lakes indicate that the species within LV continue exchanging genes. These observations have important implications for phylogenetic reconstruction. The approach used in this study is applicable to other instances of adaptive radiation.

An Alu retrotransposition-mediated deletion of CHD7 in a patient with CHARGE syndrome.

CHD7 mutations account for about 60-65% among more than 200 CHARGE syndrome cases. When rare whole gene deletion cases associated with chromosomal abnormalities are excluded, all mutations of CHD7 reported to date have been point mutations and small deletions and insertions, rather than exonic deletions. To test whether exonic deletions represent a common pathogenic mechanism, we assessed exon copy number by using a recently developed method, the multiplex PCR/liquid chromatography assay (MP/LC). Multiple exons were amplified using unlabeled primers, then separated by ion-pair reversed-phase high-performance liquid chromatography, and quantitated by fluorescence detection using a post-column intercalation dye under the premise that the relative peak intensities for each target directly reflect exon copy number. By using MP/LC, we identified one CHARGE syndrome patient who had a de novo deletion encompassing exons 8-12 among 13 classic CHARGE patients in whom screening by denaturing high-performance liquid chromatography (DHPLC) failed to identify point mutations and small insertions/deletions in CHD7. This is the first CHARGE patient who was documented to have exonic deletion of CHD7. The deletion closely recapitulated the Alu-mediated inactivation of the human CMP-N-acetylneuraminic acid hydroxylase gene (CMP-Neu5Ac hydroxylase), which is regarded as a novel molecular mechanism in the evolution from non-human primates to humans. As demonstrated in this study, MP/LC is a promising method for characterizing exonic deletions, which are largely left unexamined in most routine mutation analysis.

The origin and evolution of human ampliconic gene families and ampliconic structure.

Out of the nine male-specific gene families in the human Y chromosome amplicons, we investigate the origin and evolution of seven families for which gametologous and orthologous sequences are available. Proto-X/Y gene pairs in the original mammalian sex chromosomes played major roles in origins and gave rise to five gene families: XKRY, VCY, HSFY, RBMY, and TSPY. The divergence times between gametologous X- and Y-linked copies in these families are well correlated with the former X-chromosomal locations. The CDY and DAZ families originated exceptionally by retroposition and transposition of autosomal copies, respectively, but CDY possesses an X-linked copy of enigmatic origin. We also investigate the evolutionary relatedness among Y-linked copies of a gene family in light of their ampliconic locations (palindromes, inverted repeats, and the TSPY array). Although any pair of copies located at the same arm positions within a palindrome is identical or nearly so by frequent gene conversion, copies located at different arm positions are distinctively different. Since these and other distinct copies in various gene families were amplified almost simultaneously in the stem lineage of Catarrhini, we take these simultaneous amplifications as evidence for the elaborate formation of Y ampliconic structure. Curiously, some copies in a gene family located at different palindromes exhibit high sequence similarity, and in most cases, such similarity greatly extends to repeat units that harbor these copies. It appears that such palindromic repeat units have evolved by and large en bloc, but they have undergone frequent exchanges between palindromes.

Further evidence for recombination between mouse hemoglobin beta b1 and b2 genes based on the nucleotide sequences of intron, UTR, and intergenic spacer regions.

Nucleotide sequences of the intron regions and UTRs (Untranslated regions) of the hemoglobin beta adult genes, b1 and b2, and of the intergenic spacer region were determined for mouse strains representing the d, p, and w1 hemoglobin haplotypes defined by protein electrophoretic analyses. The hypothesis of recombination of the b1 and b2 genes between the d and w1 haplotypes previously reported in the cDNA nucleotide sequences was confirmed by neighbor-joining analyses of the intron regions and UTRs within the b1 and b2 genes, suggesting that all of the structures of hemoglobin beta adult genes support the hypothesis that the p haplotype was established by hybridization between d and w1 haplotype mice. The resultant recombinant of the p haplotype was found to have a d-like b1 gene and a w1-like b2 gene. In addition to the possible recombination, a break point was suggested around 2-3 kb downstream of the b1 gene within the intergenic spacer region, despite the absence of clear properties that could stimulate the recombination machinery. Some large insertions or deletions (indels) specific to the p or d haplotypes were located within the intergenic spacer region, in which the 1010-bp indel specific to the p haplotype was shared by all examined strains representing the p haplotype.