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PubMed2024

FLT4 gene polymorphisms influence isolated ventricular septal defect predisposition in a Southwest China population.

BACKGROUND: Ventricular septal defect (VSD) is the most common congenital heart disease. Although a small number of genes associated with VSD have been found, the genetic factors of VSD remain unclear. In this study, we evaluated the association of 10 candidate single nucleotide polymorphisms (SNPs) with isolated VSD in a population from Southwest China. METHODS: Based on the results of 34 congenital heart disease whole-exome sequencing and 1000 Genomes databases, 10 candidate SNPs were selected. A total of 618 samples were collected from the population of Southwest China, including 285 VSD samples and 333 normal samples. Ten SNPs in the case group and the control group were identified by SNaPshot genotyping. The chi-square (χ2) test was used to evaluate the relationship between VSD and each candidate SNP. The SNPs that had significant P value in the initial stage were further analysed using linkage disequilibrium, and haplotypes were assessed in 34 congenital heart disease whole-exome sequencing samples using Haploview software. The bins of SNPs that were in very strong linkage disequilibrium were further used to predict haplotypes by Arlequin software. ViennaRNA v2.5.1 predicted the haplotype mRNA secondary structure. We evaluated the correlation between mRNA secondary structure changes and ventricular septal defects. RESULTS: The χ2 results showed that the allele frequency of FLT4 rs383985 (P = 0.040) was different between the control group and the case group (P < 0.05). FLT4 rs3736061 (r2 = 1), rs3736062 (r2 = 0.84), rs3736063 (r2 = 0.84) and FLT4 rs383985 were in high linkage disequilibrium (r2 > 0.8). Among them, rs3736061 and rs3736062 SNPs in the FLT4 gene led to synonymous variations of amino acids, but predicting the secondary structure of mRNA might change the secondary structure of mRNA and reduce the free energy. CONCLUSIONS: These findings suggest a possible molecular pathogenesis associated with isolated VSD, which warrants investigation in future studies.

Child↗

PubMed1978

Site specificity and variability in the mutator and antimutator effects of phage T4 gene 43 mutants.

Spontaneous, 2-aminopurine- and 5-bromouracil-induced mutations at six rII nonsense codons were studied in phage T4 strains possessing wild-type and mutant gene 43 alleles. The mutation pathways studied included interconversions and reversions of nonsense codons. The tsCB87 allele, which specifies an antimutator DNA polymerase, reduced base-analogue-induced mutation frequencies along all pathways. However, GC base pairs were less affected than AT base pairs. The frequency of spontaneous UAA leads to UAG conversions was also reduced by tsCB87, but that of spontaneous UAA leads to UAG UGA conversions was often increased. Mutation in the presence of the mutator allele tsL56 was increased along all pathways, with no preference for either AT or GC base pairs. Mutation frequencies in the presence of the two mutant DNA polymerases were highly variable. A strong correlation was found between 2-aminopurine-induced mutation frequencies in ts+ tsCB87 phage along the reversion and UAA changed to UAG (but not UAA changed to UGA) pathways.

2-Aminopurine↗

PubMed2026

The Spatial and Temporal Repeatability of Genomic Responses to Natural Selection as Demonstrated in Stickleback Populations Experiencing Highly Dynamic Environments.

The evolution of genotypic parallelism under shared environmental conditions provides strong evidence for the role of natural selection. However, analyses typically examine genomic signatures of selection long after the putative selection event and only assess the repeatability of responses across spatial population replicates. This impedes our ability to attribute a particular response to a given selection pressure and to distinguish non-parallel responses caused by stochastic processes from those caused by local selection. As such, the consistency of natural selection over space and time is unknown, and the role of persistent local selection pressures is unclear. Here, we leveraged the natural bar-built estuary system of Santa Cruz, California, to examine the repeatability of seasonal genomic change in threespine stickleback (Gasterosteus aculeatus) over space and time. By comparing allele-frequency shifts that are shared across locations (spatial repeatability) with those that are shared across years within locations (temporal repeatability), we identified both spatially shared and local components of putative selection. We found that repeated seasonal outlier responses occurred more often than expected under a neutral null model. Although repeatability declined as the number of estuaries sharing an outlier increased, enrichment above neutral expectations increased with broader spatial sharing, particularly for outliers repeated across both years. While the precise outlier SNPs varied across years, estuary-specific patterns of responses were broadly consistent, suggesting an important role for local conditions. Together, our findings show that temporal sampling can reveal components of putative selection that would be missed from spatial comparisons alone. More broadly, they highlight the importance of examining repeatability over both space and time to understand the parallel and non-parallel components of adaptive genomic change.

Animals↗

PubMed1978

Biochemical genetics of Fundulus heterolitus (L.). I. Temporal and spatial variation in gene frequencies of Ldh-B, Mdh-A, Gpi-B, and Pgm-A.

Natural populations of Fundulus heteroclitus show extensive spatial variation in gene frequencies at four unlinked polymorphic loci. Large clinal changes in gene frequencies were found for Ldh-B, Mdh-A, and Gpi-B, whereas the spatial variation for the Pgm-B locus was small. Since the geographical area over which these clines are found is characterized by a steep thermal gradient, the clines in gene frequency are correlated with a directional change in mean water temperature. Maximum gene diversity of these four loci was correlated with annual fluctuations in water temperature. Temporal stability of the allelic frequencies was established for a 2--4 year period.

Animals↗

PubMed1979

Polygamy and the evolution of human longevity.

An alternative to previous explanations of the rapid increase in man's longevity and intelligence during the several million years of his recent evolution from pre-hominid, clearly shorter-lived and less intelligent, primate ancestors is presented. The general thesis is that a very greatly accelerated rate of incorporation of favorable genes or gene combinations can be achieved in surprisingly few generations among social animals provided that dominant males become the patriarchs of many descendents by virtue of their partial or complete monopoly on available females. The conclusion is that man probably differs from his ancesters of 0.5 to 5 million years ago by many thousands of genes (both structural and regulatory) rather than the dozens or few hundreds that have been postulated on the basis of more classical treatments of selection pressures, gene frequency changes and mutation rates. The concepts developed here formally apply only to two alternative alleles, rather than to groups of genes which segregate independently, or to characters determined by multiple alleles. The appropriate mathematical treatment of the latter real situation is not readily visualized; nor is account taken of the likelihood that different tribes of pre-humans developed different specializations via the above mechanisms which were then (later) combined into an emerging human stock through matings between members of different tribes. The very great variability both in longevity and in intelligence between different races of animals such as dogs, which have been the objects of deliberate genetic selection by humans for particular heritable traits, may parallel our own recent history, even though the selection mechanism (deliberate human selection vs. polygamous dominance) is quite different in the two cases. The onset of civilizations consisting of amalgums between smaller, previously competing tribes, together with the humanitarian responsibilities to each other we share as a species, ironically has probably arrested further evolution of human longevity (and perhaps of intelligence) in the modern world. Possibly even retrogressive changes are occurring, except in those rare sub-populations in which special social and cultural practices tend to favor selective perpetuation of characteristics which are usually viewed as beneficial.

Alleles↗

PubMed2026

Ancient DNA and Human Physiology.

Ancient DNA (aDNA) enables the reconstruction of chronologically sampled genomes from ancient humans, animals, plants, pathogens, and microorganisms, as well as environmental DNA, providing a record of biological changes through time. Improvements in short and degraded DNA extraction methods and low-cost sequencing now enable the generation of broad, cross-regional datasets that expand evolutionary analyses from past population demography to biological mechanisms. By tracking temporal shifts of allele frequencies, integrating functional genomics resources (e.g., gene expression, chromatin structure variation), modeling population demography to separate selection from genetic drift, and aligning genetic changes with archaeological, cultural, and climatic data, aDNA has the potential to link sequence variation to physiological function within their temporal and environmental contexts. In this review, we summarize illustrative case studies from aDNA research spanning complex traits, dietary adaptations, and responses to pathogens and other environmental changes, showing how human biology has evolved under multiple selective pressures through time. These dated signals help triage experimental work and expose mechanisms that are rare or absent in living cohorts. Although some challenges remain, such as geographic and temporal sampling disparities, limitations in data resolution and variant detection, and genotype-phenotype uncertainties, rapid methodological progress and stronger ethical frameworks are expanding what can be inferred, making aDNA a promising tool for refining physiological pathways, their timing, and their drivers.

Humans↗

PubMed2025

Identification of Genetic Variations in HLA Region for Kidney Functions.

HLA allelic polymorphisms are associated with a variety of kidney-related traits in different populations. Although Taiwanese-specific genetic variants associated with kidney function have been reported, the role of HLA alleles is unclear. In this study, the association between eGFR and genetic variations in the HLA region was explored in a cohort of 59,448 Taiwanese subjects. A total of 448 genetic variations in the HLA region are significantly associated with eGFR. HLA-C*03 is associated with decreased eGFR, while HLA-DQA1*03, HLA-DQB1*03:03 and HLA-DQB1*03:03:02 demonstrated protective effects. Moreover, amino acid changes on HLA-C and HLA-DRB1 are significantly associated with eGFR. Finally, the eGFR-associated single nucleotide variations (SNVs) and insertions and deletions (indels) are enriched in the HLA-DQB1 gene. After conditional analysis, we identified two independent signals, including rs2853941, rs3830060. In summary, this study highlights the role of HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 variations in kidney function in the Taiwan Han Chinese population.

Adult↗

PubMed1979

Relative fitness of genotypes in a population of Rattus norvegicus polymorphic for warfarin resistance.

Resistance to warfarin and an increased vitamin K requirement appear to be pleiotropic effects of the same allele (Rw2). In a natural population containing resistant individuals where the use of warfarin is discouraged the change in the frequency of resistance should reflect the relative fitnesses of the three possible genotypes. A large polymorphic population of rats was extensively poisoned with warfarin and the level of resistance monitored regularly for a period of 18 months after withdrawal of the poison. During this period the proportion of resistant animals in live-capture samples decreased significantly from approximately 80 per cent to 33 per cent. This decline is consistent with a hypothesis of reduced fitness of both Rw2Rw2 and Rw1Rw2 genotypes relative to Rw1Rw1 under natural conditions. The relative fitnesses of these genotypes were calculated using an optimisation method based on least squares analysis. These estimates were: Rw2Rw2 (0.46), Rw1Rw2 (0.77) and Rw1Rw1 (1.00). Homozygous resistant individuals were found in some of the samples, confirming that the Rw2 allele does not act as a recessive lethal, although it must be extremely disadvantageous. Some heterogeneity was observed in the proportion of resistant animals in samples taken from different areas of the farm building complex. This could reflect stochastic processes influencing the Rw2 allele frequency in small peripheral populations.

Animals↗

PubMed2026

Faster inference of complex demographic models from large allele frequency spectra.

MOTIVATION: Demographic inference from the joint site frequency spectrum is limited by computation when many populations or many samples are analyzed. RESULTS: We present momi3, a JAX-based method for inferring complex demographic models from large allele frequency spectra. It supports continuous migration, GPU execution, automatic differentiation, standardized demographic model input, and genealogical pruning. These changes yield speedups up to 1000× over existing methods and enable analysis of archaic admixture models using hundreds of human genomes. AVAILABILITY AND IMPLEMENTATION: momi3 is implemented in Python/JAX as part of demestats. Source code is available at https://github.com/jthlab/demestats; documentation is available at https://demestats.readthedocs.org.

Humans↗

PubMed2025

Rapid Divergence of Visual Systems and Signaling Traits to Contrasting Light Regimes During Early Speciation of African Crater Lake Cichlid Fish.

Sensory adaptation is widely hypothesized to drive ecological speciation, yet empirical evidence from natural populations undergoing early stage divergence remains limited. In Lake Masoko, a young crater lake in East Africa, the haplochromine cichlid Astatotilapia calliptera is undergoing early stage sympatric speciation into shallow-water littoral and deep-water benthic ecotypes that experience contrasting light environments. Here, we integrate retinal transcriptomics, phenotypic analyses, and visual modeling to uncover rapid sensory divergence associated with this ecological transition. We find striking shifts in cone opsin expression, with the benthic ecotype exhibiting a switch from short-wavelength sensitive SWS2B to SWS2A and an overall narrowing of cone sensitivity toward the center of the light spectrum, consistent with changes in deep-water light environment. In contrast, coding sequence variation in opsin genes was limited and no significant differences in allele frequencies were detected across nine polymorphic sites, pointing to expression regulation as the primary axis of early divergence in visual systems. In parallel, we observed divergence in male signaling traits, with benthic males displaying deeper red egg-spots, aligning with predictions from visual modeling of signal efficiency in different light environments. These results demonstrate rapid transcriptomic and phenotypic divergence in associated signaling traits-within ∼1,000 years-supporting a potential role for regulatory evolution in sensory adaptation during early ecological speciation.

Animals↗

PubMed2026

Virus-induced gene editing of stomatal regulators in Nicotiana benthamiana enables rapid functional genomics.

Virus-induced gene editing (VIGE) holds promise as a rapid and scalable approach for functional genomics in plants. Here, we apply a tobacco rattle virus (TRV)-based single-guide RNA (sgRNA) delivery system to target key regulators of stomatal development in Nicotiana benthamiana using transgenic Cas9-expressing lines. sgRNAs fused to a mobile RNA element and co-delivered with TRV enabled both somatic and heritable genome editing across orthologs of STOMAGEN, EPF2, YODA, and SPEECHLESS. Somatic editing frequencies reached up to 95%, and heritable tetra-allelic mutations were recovered in multiple target genes. Mutants exhibited significant, gene-specific changes in stomatal density, with corresponding effects on leaf temperature indicative of altered evaporative cooling. Additionally, sgRNAs fused to an AmCyan reporter enabled visualization of virus-infected tissues, allowing stomatal phenotyping in edited M0 sectors. This TRV-based platform facilitates functional assessment of genes influencing stomatal patterning and offers a powerful tool for dissecting gene function in a developmentally and physiologically relevant context.

Nicotiana↗

PubMed1977

Blood antigen, serum protein, and milk protein gene frequencies and genetic interrelationships in Holstein cattle.

Gene frequencies at ten blood group loci, one serum protein locus, and four milk protein loci were determined for the Holstein-Friesian breed in the United States. The sample consisted of 8630 cows in 51 herds from 10 states. Because of the close linkage among casein subloci and the concimitant rarity of crossover-recombinant groups, casein gene combination or haplotype frequencies were determined also. As one means of comparison of systems, indices of homozygosity and number of effective alleles were calculated. These indices were proposed also to be useful tools for monitoring changes in genetic variability of breeds. Genotypes within codominant systems and phenotypes associated with paired-system combinations generally were not randomly occurring. Paired system phenotypes within the sire sample corresponded much more closely to expectations of randomness.

Alleles↗

PubMed1978

Distribution of albumin variants Naskapi amd Mexico among Aleuts, Frobisher Bay Eskimos, and Micmac, Naskapi, Mohawk, Omaha, and Apache Indians.

In order to help define the boundaries of the distribution of the albumin variants Naskapi and Mexico which are polymorphic among several American Indian groups, we examined sera from Micmac, Mohawk, Northwest River Naskapi, Omaha and Apache Indians, and from Aleuts and Eskimos. Sera from a total of 1,524 individuals were examined. Using a cellulose acetate membrane electrophoretic system with Tris-Citric acid at pH 5.4 we were able to distinguish normal albumin and both variants in the same run. Naskapi and Mexico variants were absent from Aleut, Eskimo, Micmac, Mohawk and Omaha samples. The albumin Naskapi variant was present in an allele frequency of 0.03 in the Naskapi Indian sample. Albumin variants Naskapi and Mexico were found in the Apache sample at frequencies of 0.016 and 0.037, respectively. This report supersedes that previously published by Schell and Agarwal ('76). Generally, within an area there is a correspondence between changes in the frequency of albumin variants and changes in the ethnic background and history of the area's populations. At the same time, when viewing widely separated areas, relationships between distant groups based on linguistic and cultural similarities are paralleled on a biologic level by the distribution of normal albumin and variant albumins.

Alleles↗

PubMed1975

Ethnic variation in genetic disease: possible roles of hitchhiking and epistasis.

The high incidence of some genetic diseases in certain ethnic groups is important in planning of medical genetic programs. Simple interaction models predict that at least some lethal recessive alleles will have "hitchhiked" to increased frequencies because of linkage to genes whose alleles have been favored by selection for other reasons in certain populations. In the absence of linkage or epistasis with a gene favored by selection, heterozygote advantage for a recessive lethal may produce the same phenomenon. In the hitchhiking model (linkage), the increase in the gene frequency is temporary, but the length of time that the increased gene frequency is at least double the base frequency may be quite long. Changes in gene frequency for the unlinked epistatic model result in a new equilibrium with a possibly higher gene frequency. The most likely chromosomal regions in which hitchhiked lethal recessives would be found are in the vicinity of genes whose allelic frequencies vary substantially among human racial groups (e.g., Gm, Rh, Duffy, lactose tolerance, or HL-A). There will be a hitchhiking effect if recombination distance is less than the selective advantage. The closer the linkage of two loci, the easier hitchhiking effects will be to detect. Hitchhiking is suggested by nonrandom association of the recessive disease and one of the selected markers, as in the case of Gm and cystic fibrosis. However, there is so far insufficient evidence of linkage between them. More pedigree information is necessary than is now available.

Alleles↗

PubMed2026

A dominant mutation in tomato DNA POLYMERASE DELTA 1 causes geminivirus DNA replication catastrophe.

Geminiviruses pose a severe threat to grain and vegetable crops worldwide, often resulting in significant economic losses. In cultivated tomato (Solanum lycopersicum), Ty resistance alleles have been introduced from wild tomato relatives, providing partial to strong resistance to geminivirus infections. The Ty-6 resistance locus from Solanum chilense was previously mapped to chromosome 10. It was recently shown to contain a mutant allele of the DNA POLYMERASE DELTA 1 (POLD1) gene that provides resistance to Tomato yellow leaf curl virus (TYLCV) infections. However, the resistance mechanism remained unknown. Here, we report another POLD1 allele at the Ty-6 locus of S. chilense with an E622D mutation in the catalytic site of the POLD1 protein. POLD1E622D is maintained as a heterozygous dominant allele in S. chilense and the AVTO2225 breeding line. It provides full resistance to the severe TYLCV Thailand (TYLCTHV) strain. The E622D amino acid change does not alter the predicted structure of POLD1. Replication of the TYLCTHV genome in plants carrying the POLD1E622D allele is severely compromised by a high frequency of mutations that accumulate in viral DNA, which results in nonfunctional proteins that are essential for continuous viral replication. Ectopically expressing the POLD1E622D allele cDNA alone causes mutations in TYLCTHV genes in inoculated leaves. S. chilense and AVTO2225 plants carrying the POLD1E622D allele mount a hypersensitive response after TYLCTHV infection, indicating that the defective virus genome cannot suppress the plant defense. The dominant POLD1E622D allele is therefore an effective resistance gene that geminiviruses cannot overcome.

DNA Replication↗

PubMed1979

Gene frequency and fitness change in an age-structured population.

Fisher's system of reproductive value weighting, whereby each age group is assigned a weight purported to measure its contribution to the ancestry of future generations, was suggested by him as a way of ironing out irregularities in the change of population numbers when the age structure is not in equilibrium. This has been extended to Mendelian populations for two models. In Model I, the reproductive value of each genotype is computed from a table of age-specific survival and reproduction rates, and the genic values are computed by averaging these genotypic values. The total reproductive value of an allele and of the population always increase at a rate equal to the reproductive value-weighted average fitness regardless of age structure. This has the disadvantage that the total reproductive value is not equal to the census numbers, when age-stability has been reached. In Model II, this difficulty is surmounted, but the formula is no longer exact. The reproductive value of an allele for a specific age x is measured from the average death and reproductive rates of individuals of age x carrying that allele. An expression is given for the rate of change of reproductive value of an allele or of the population. In many circumstances this changes nearly uniformly, regardless of irregularities of age structure, and goes over to the census numbers as age stability is approached. The special difficulties in populations with separate sexes are discussed and a formula for rate of change of mean reproductive value, analogous to Fisher's Fundamental Theorem of Natural Selection, is given.

Age Factors↗

PubMed1979

Evolutionary potential: a mathematical hypothesis of mouse hemoglobin beta chain evolution.

This paper examines the possibility that the linkage arrangements and regulatory properties of genes may be influenced by selection. A mathematical hypothesis is developed in order to show how selective properties of hemoglobin beta chains could have influenced the linkage and regulation of their structural genes. The hypothesis is applied to the case of mouse hemoglobin beta chains. In most mice, closely-linked pairs of loci (doublets) code for two structurally divergent beta chains in unequal amounts. Some mouse strains have singlet alleles, however, coding for another beta chain variant. With the mathematical hypothesis, one can show that selectively determined "evolutionary potentials" may have favored changes in proportions of major and minor chains produced by a doublet allele. In the extreme case, zero production of the minor chain may give a selective advantage, leading to a singlet; conversely, selection may favor linking another gene to the singlet locus to give a doublet. A specific prediction of the model is the stable maintenance under certain conditions of multiple alleles at regulatory loci. The concept of evolutionary potential thus suggests that selection could have influenced the evolution of genotypic fitnesses, in addition to causing changes in gene frequencies as in standard population genetics models

Animals↗

PubMed1978

Ancestral inference. II. The founders of Tristan da Cunha.

The Tristan da Cunha data for the MN-blood types and for retinitis pigmentosa are analysed according to the methods for ancestral inference developed in the preceding paper. Joint and marginal likelihoods for the MN data show that it is possible to make inferences about the types of original founder genes, although relative values are in some cases not large. Although relative likelihoods are robust against small changes in gene frequency, they can be distorted by assuming values that differ widely from the maximum likelihood estimate. In the case of retinitis pigmentosa, under an assumed allele frequency of 0.01, we conclude, contrary to expectations, that the couple (975, 798) are substantially the most likely founders to have been responsible for the introduction of the allele. The inferences for this trait are complicated by the fact that it is recessive, and genotypes are therefore not observable. Extinction probabilities for a variety of sets of original founder genes on the Tristan da Cunha ancestral pedigree are also computed and discussed.

Alleles↗