Population Genetic Factors Research Articles

How do gap dynamics and colonization of a human disturbed area affect genetic diversity and structure of a pioneer tropical tree species?

Pioneer tree species exhibit life-cycle characteristics and population structures that are mainly affected by natural or human disturbances. In primary forests, demographic dynamics of pioneer species may resemble those defined for a metapopulation. In early successional forests, the patterns of establishment, survival and reproduction are mainly determined by microclimate and biota modifications of the site after the human disturbance. The aim of this study was to investigate how the ecological processes and the population genetic factors associated with disturbances can affect the genetic diversity and structure of populations of a pioneer tree species: Croton floribundus Spreng. (Euphorbiaceae). Nuclear and chloroplast microsatellite markers were examined in plants of two size classes sampled in four gaps of primary forest and four sub-areas of early successional forest. Despite presenting similar genetic diversity levels, the genetic diversity was distributed differently between forests. The combined effects of seed dispersal and colonizations (and extinctions) were determinants of the fine-scale genetic structure of C. floribundus. The main finding was that human disturbances seem to boost the influence of founder effects in populations of a species with limited seed dispersal. Results suggested that gene flow by pollen was responsible for maintaining the genetic diversity within populations of C. floribundus in both forests, but in the early successional forest, gene flow by seeds was equally important. We conclude that gap dynamics, colonization, and pollen and seed dispersal affect the genetic diversity and structure of the pioneer species depending mainly on the number of colonizers, the number of source populations, the gene flow rates, and the level of human disturbance.

No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans.

Non-African populations have experienced size reductions in the time since their split from West Africans, leading to the hypothesis that natural selection to remove weakly deleterious mutations has been less effective in the history of non-Africans. To test this hypothesis, we measured the per-genome accumulation of non-synonymous substitutions across diverse pairs of populations. We find no evidence for a higher load of deleterious mutations in non-Africans. However, we detect significant differences among more divergent populations, as archaic Denisovans have accumulated non-synonymous mutations faster than either modern humans or Neanderthals. To reconcile these findings with patterns that have been interpreted as evidence of less effective removal of deleterious mutations in non-Africans than in West Africans, we use simulations to show that the observed patterns are not likely to reflect changes in the effectiveness of selection after the populations split, and instead are likely to be driven by other population genetic factors.

Association between Helicobacter spp. infections and hepatobiliary malignancies: a review.

Hepatobiliary cancers are highly lethal cancers that comprise a spectrum of invasive carcinomas originating in the liver hepatocellular carcinoma, the bile ducts intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, the gallbladder and the ampulla of Vater (collectively known as biliary tract cancers). These tumors account for approximately 13% of all annual cancer-related deaths worldwide and for 10%-20% of deaths from hepatobiliary malignancies. Cholangiocarcinoma (CCA) is a devastating disease that displays a poor survival rate for which few therapeutic options are available. Population genetics, geographical and environmental factors, cholelithiasis, obesity, parity, and endemic infection with liver flukes have been identified as risk factors that influence the development of biliary tract tumors. Other important factors affecting the carcinogenesis of these tumors include chronic inflammation, obstruction of the bile ducts, and impaired bile flow. It has been suggested that CCA is caused by infection with Helicobacter species, such as Helicobacter bilis and Helicobacter hepaticus, in a manner that is similar to the reported role of Helicobacter pylori in distal gastric cancer. Due to the difficulty in culturing these Helicobacter species, molecular methods, such as polymerase chain reaction and sequencing, or immunologic assays have become the methods of choice for diagnosis. However, clinical studies of benign or malignant biliary tract diseases revealed remarkable variability in the methods and the findings, and the use of uniform and validated techniques is needed.

No evidence for rare recessive and compound heterozygous disruptive variants in schizophrenia.

Recessive inheritance of gene disrupting alleles, either through homozygosity at a specific site or compound heterozygosity, have been demonstrated to underlie many Mendelian diseases and some complex psychiatric disorders. On the basis of exome sequencing data, an increased burden of complete knockout (homozygous or compound heterozygous) variants has been identified in autism. In addition, using single-nucleotide polymorphism microarray data, an increased rate of homozygosity by descent, or autozygosity, has been linked to the risk of schizophrenia (SCZ). Here, in a large Swedish case-control SCZ sample (11 244 individuals, 5079 of whom have exome sequence data available), we survey the contribution of both autozygosity and complete knockouts to disease risk. We do not find evidence for association with SCZ, either genome wide or at specific loci. However, we note the possible impact of sample size and population genetic factors on the power to detect and quantify any burden that may exist.

Genes associated with SLE are targets of recent positive selection.

The reasons for the ethnic disparities in the prevalence of systemic lupus erythematosus (SLE) and the relative high frequency of SLE risk alleles in the population are not fully understood. Population genetic factors such as natural selection alter allele frequencies over generations and may help explain the persistence of such common risk variants in the population and the differential risk of SLE. In order to better understand the genetic basis of SLE that might be due to natural selection, a total of 74 genomic regions with compelling evidence for association with SLE were tested for evidence of recent positive selection in the HapMap and HGDP populations, using population differentiation, allele frequency, and haplotype-based tests. Consistent signs of positive selection across different studies and statistical methods were observed at several SLE-associated loci, including PTPN22, TNFSF4, TET3-DGUOK, TNIP1, UHRF1BP1, BLK, and ITGAM genes. This study is the first to evaluate and report that several SLE-associated regions show signs of positive natural selection. These results provide corroborating evidence in support of recent positive selection as one mechanism underlying the elevated population frequency of SLE risk loci and supports future research that integrates signals of natural selection to help identify functional SLE risk alleles.

Population-Genetic Influences on Genomic Estimates of the Inbreeding Coefficient: A Global Perspective

Background/Aims: Culturally driven marital practices provide a key instance of an interaction between social and genetic processes in shaping patterns of human genetic variation, producing, for example, increased identity by descent through consanguineous marriage. A commonly used measure to quantify identity by descent in an individual is the inbreeding coefficient, a quantity that reflects not only consanguinity, but also other aspects of kinship in the population to which the individual belongs. Here, in populations worldwide, we examine the relationship between genomic estimates of the inbreeding coefficient and population patterns in genetic variation. Methods: Using genotypes at 645 microsatellites, we compare inbreeding coefficients from 5,043 individuals representing 237 populations worldwide to demographic consanguinity frequency estimates available for 26 populations as well as to other quantities that can illuminate population-genetic influences on inbreeding coefficients. Results: We observe higher inbreeding coefficient estimates in populations and geographic regions with known high levels of consanguinity or genetic isolation and in populations with an increased effect of genetic drift and decreased genetic diversity with increasing distance from Africa. For the small number of populations with specific consanguinity estimates, we find a correlation between inbreeding coefficients and consanguinity frequency (r = 0.349, p = 0.040). Conclusions: The results emphasize the importance of both consanguinity and population-genetic factors in influencing variation in inbreeding coefficients, and they provide insight into factors useful for assessing the effect of consanguinity on genomic patterns in different populations.

Re-Examining Racial Disparities in Prostate Cancer Outcomes

Re-Examining Racial Disparities in Prostate Cancer Outcomes

Estimating and interpreting FST: The impact of rare variants

In a pair of seminal papers, Sewall Wright and Gustave Malécot introduced FST as a measure of structure in natural populations. In the decades that followed, a number of papers provided differing definitions, estimation methods, and interpretations beyond Wright's. While this diversity in methods has enabled many studies in genetics, it has also introduced confusion regarding how to estimate FST from available data. Considering this confusion, wide variation in published estimates of FST for pairs of HapMap populations is a cause for concern. These estimates changed—in some cases more than twofold—when comparing estimates from genotyping arrays to those from sequence data. Indeed, changes in FST from sequencing data might be expected due to population genetic factors affecting rare variants. While rare variants do influence the result, we show that this is largely through differences in estimation methods. Correcting for this yields estimates of FST that are much more concordant between sequence and genotype data. These differences relate to three specific issues: (1) estimating FST for a single SNP, (2) combining estimates of FST across multiple SNPs, and (3) selecting the set of SNPs used in the computation. Changes in each of these aspects of estimation may result in FST estimates that are highly divergent from one another. Here, we clarify these issues and propose solutions.

Brain Activation of SIRT1: Role in Neuropathology

Sirtuins (SIRTs) are a family of regulatory proteins of genetic information with a high degree of conservation among species. The SIRTs are heavily involved in several physiological functions including control of gene expression, metabolism, and aging. SIRT1 has been the most studied sirtuin and plays important role in the prevention and progression of neurodegenerative diseases acting in different pathways of proteins involved in brain function. SIRT1 activation regulates important genes that also exert neuroprotective actions such as p53, nuclear factor kappa B, peroxisome proliferator-activated receptor-gamma (PPARγ), PPARγ coactivator-1α, liver X receptor, and forkhead box O. It is well established in literature that growing population aging, oxidative stress, inflammation, and genetic factors are important conditions to development of neurodegenerative disorders. However, the exact pathophysiological mechanisms leading to these diseases remain obscure. The sirtuins show strong potential to become valuable predictive and prognostic markers for diseases and as therapeutic targets for the treatment of a variety of neurodegenerative disorders. In this context, the aim of the current review is to present an actual view of the potential role of SIRT1 in modulating the interaction between target genes and neurodegenerative diseases on the brain.

Effects of environmental factors on the population genetic diversity of Chinese bamboo partridge (Bambusicola thoracica)

Knowledge of factors that affect population demographic and genetic diversity is of importance to understand the evolutionary ecology. The environment plays an important role in the evolutionary process. This study used mtDNA control region sequences and nuclear microsatellites to infer the relationship between population genetic diversity and environmental factors of Chinese bamboo partridge (Bambusicola thoracica). A total of 1140 nucleotides of mitochondrial DNA control region were sequenced from 180 bamboo partridge sampled from thirteen populations in southeast China. Thirteen-nine polymorphic positions defined 50 haplotypes. The ten microsatellite loci were polymorphic in all populations of Chinese bamboo partridge. Bamboo partridge population genetic diversity (π-, h-, K-, HE- and HO- values) decreased with decreasing variation coefficients of temperature and rainfall. The more stable the climate, the higher the genetic diversity observed. Key words: Bambusicola thoracica, mitochondrial DNA, microsatellite, genetic diversity, environmental factors.

The population genetics of cooperative gene regulation

BackgroundChanges in gene regulatory networks drive the evolution of phenotypic diversity both within and between species. Rewiring of transcriptional networks is achieved either by changes to transcription factor binding sites or by changes to the physical interactions among transcription factor proteins. It has been suggested that the evolution of cooperative binding among factors can facilitate the adaptive rewiring of a regulatory network.ResultsWe use a population-genetic model to explore when cooperative binding of transcription factors is favored by evolution, and what effects cooperativity then has on the adaptive re-writing of regulatory networks. We consider a pair of transcription factors that regulate multiple targets and overlap in the sets of target genes they regulate. We show that, under stabilising selection, cooperative binding between the transcription factors is favoured provided the amount of overlap between their target genes exceeds a threshold. The value of this threshold depends on several population-genetic factors: strength of selection on binding sites, cost of pleiotropy associated with protein-protein interactions, rates of mutation and population size. Once it is established, we find that cooperative binding of transcription factors significantly accelerates the adaptive rewiring of transcriptional networks under positive selection. We compare our qualitative predictions to systematic data on Saccharomyces cerevisiae transcription factors, their binding sites, and their protein-protein interactions.ConclusionsOur study reveals a rich set of evolutionary dynamics driven by a tradeoff between the beneficial effects of cooperative binding at targets shared by a pair of factors, and the detrimental effects of cooperative binding for non-shared targets. We find that cooperative regulation will evolve when transcription factors share a sufficient proportion of their target genes. These findings help to explain empirical pattens in datasets of transcription factors in Saccharomyces cerevisiae and, they suggest that changes to physical interactions between transcription factors can play a critical role in the evolution of gene regulatory networks.

Five-Year Longitudinal Assessment of the Downstream Impact on Schistosomiasis Transmission following Closure of the Three Gorges Dam

Background Schistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with about 800,000 people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that, long-term, the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes.Methodology/Principal FindingsWe undertook longitudinal surveillance from 2002 to 2006 in sentinel villages of the three transmission modes below the TGD across four provinces (Hunan, Jiangxi, Hubei and Anhui) to determine whether there was any immediate impact of the TGD on schistosomiasis transmission. Eight sentinel villages were selected to represent both province and transmission mode. The primary end point measured was human incidence. Here we present the results of this five-year longitudinal cohort study. Results showed that the incidence of human S. japonicum infection declined considerably within individual villages and overall mode over the course of the study. This is also reflected in the yearly odds ratios (adjusted) for infection risk that showed significant (P<0.01) downward trends in all modes over the follow-up period.Conclusions/SignificanceThe decrease in human S. japonicum incidence observed across all transmission modes in this study can probably be attributed to the annual human and bovine PZQ chemotherapy. If an increase in schistosome transmission had occurred as a result of the TGD, it would be of negligible size compared to the treatment induced decline seen here. It appears therefore that there has been virtually no immediate impact of the TGD on schistosomiasis transmission downstream of the dam.

POPULATION GENETICS OF THE WHITE-PHASED “SPIRIT” BLACK BEAR OF BRITISH COLUMBIA

The Spirit (or Kermode) bear is a white-phased black bear found on the northwest coast of British Columbia, and is one of the most striking color polymorphisms found in mammals. A single nucleotide polymorphism at the melanocortin 1 receptor gene (mc1r) locus is the cause of this recessive w variant. Recently, evidence suggests that the white color provides a selective advantage during salmon hunting. Here we examine the effects of favorable selection, gene flow, genetic drift, and positive-assortative mating in an effort to understand the establishment and maintenance of this polymorphism and the observed heterozygote deficiency for mc1r but not for microsatellite loci. It appears that genetic drift was important in the establishment of the w allele and that the selective advantage was important to counteract immigration from populations without the w allele. Positive-assortative mating can result in a deficiency of heterozygotes but needs to be quite high to result in the large deficiency of heterozygotes observed, suggesting that other factors must also be contributing. Examination of population genetic factors, singly and jointly, provides insight into the establishment and maintenance of this unusual polymorphism.

A 5-year longitudinal study of schistosomiasis transmission in Shian village, the Anning River Valley, Sichuan Province, the Peoples' Republic of China

BackgroundSchistosoma japonicum is a major public health concern in the Peoples' Republic of China (PRC), with over one million people infected and another 50 million living in areas at risk of infection. Based on ecological, environmental, population genetic and molecular factors, schistosomiasis transmission in PRC can be categorised into four discrete ecosystems or transmission modes. It is predicted that the Three Gorges Dam (TGD) will impact upon the transmission of schistosomiasis in the PRC, with varying degree across the four transmission modes. We undertook longitudinal surveillance from 2002 to 2006 in sentinel villages both above and below the TGD across five provinces (Hunan, Jiangxi, Hubei, Anhui and Sichuan) to determine whether there was any impact of the TGD on schistosomiasis transmission during its construction. Here we present the results from a schistosomiasis-endemic village located above the dam in Sichuan Province.ResultsBaseline results showed a human S. japonicum prevalence of 42.0% (95% CI: 36.6-47.5). At follow-up, results showed that the incidence of S. japonicum infection in the selected human cohort in Shian decreased by three quarters from 46% in 2003 to 11.3% in 2006. A significant (P < 0.01) downward trend was also evident in the yearly adjusted (for water contact) odds ratios. Over the four years of follow-up, the incidence of S. japonicum infection in bovines declined from 11.8% in the first year to zero in the final year of follow-up.ConclusionsThe substantial decrease in human (75%) and bovine (100%) incidence observed in Shian village can probably be attributed to the annual human and bovine PZQ treatment of positives; as seen in drug (PZQ) intervention studies in other parts of PRC. If an increase in schistosome transmission had occurred as a result of the TGD, it would be of negligible size compared to the treatment induced decline seen here. It appears therefore that the construction of the TGD had virtually no impact on schistosomiasis transmission in Shian village over the period of study. Furthermore, contrary to previous reports from Sichuan downplaying the role of animals in human schistosome transmission, bovines may indeed play a role.

Genetic Epidemiology of Tuberculosis Susceptibility: Impact of Study Design

Several candidate gene studies have provided evidence for a role of host genetics in susceptibility to tuberculosis (TB). However, the results of these studies have been very inconsistent, even within a study population. Here, we review the design of these studies from a genetic epidemiological perspective, illustrating important differences in phenotype definition in both cases and controls, consideration of latent M. tuberculosis infection versus active TB disease, population genetic factors such as population substructure and linkage disequilibrium, polymorphism selection, and potential global differences in M. tuberculosis strain. These considerable differences between studies should be accounted for when examining the current literature. Recommendations are made for future studies to further clarify the host genetics of TB.

Haematological and biochemical reference intervals for infants and children in Gabon

To establish reference intervals for major haematological and biochemical parameters in Gabonese infants and children. The reference sample population consisted of 226 healthy infants (4-9 weeks of age) and 185 healthy children (18-60 months of age). Basic red cell parameters as well as total and differential white blood cell counts were performed. Clinical chemistry parameters consisted of glutamate-pyruvic transaminase and creatinine, and total bilirubin was measured in children. Statistical analysis was based on the guidelines of the Clinical and Laboratory Standards Institute. Nonparametric methods were used to determine 95% reference limits and their 90% confidence intervals. Compared to European populations, values for several red cell parameters (haemoglobin, haematocrit, red blood cell count, mean corpuscular volume) were lower and platelet counts were higher. Eosinophils were higher in the older age group, most likely caused by intestinal helminths. The study confirms the importance of establishing reference limits for local populations. The reference ranges could be used as a benchmark for similar populations in Central Africa.

Tuberculosis as a complex trait: impact of genetic epidemiological study design

Several studies have suggested a role for human genetic risk factors in the susceptibility to developing tuberculosis (TB). However, results of these studies have been inconsistent, and one potential reason for these inconsistencies is variation in aspects of study design. Specifically, phenotype definitions and population genetic factors have varied dramatically. Since TB is a complex trait, there are many challenges in designing studies to assess appropriately human genetic risk factors for the development of TB as opposed to the acquisition of latent M. tuberculosis infection. In this review we summarize these important study design differences, with illustrations from the TB genetics literature. We cite specific examples of studies of the NRAMP1 (SLC11A1) gene and present Fisher's combined p values for different stratifications of these studies to further illustrate the impact of study design differences. Finally, we provide suggestions for the design of future genetic epidemiological studies of TB.

Spatial and Temporal Variation in Vector Competence of Culex pipiens and Cx. restuans Mosquitoes for West Nile Virus

Vector competence, the probability that a vector will transmit a pathogen after feeding on an infected host, is known to vary among vector species, populations, days since feeding, and temperature during the extrinsic incubation period. However, the extent of spatio-temporal variability and consistency in vector competence of populations is not known. We examined vector competence of Culex pipiens Linnaeus and Cx. restuans Theobald mosquitoes for West Nile virus collected over 3 years from 17 sites to measure spatial and temporal scales of variation in vector competence. We found extreme variation with 0-52% of mosquitoes transmitting West Nile virus at a single site between different sampling periods, and similar variation across populations. However, we also found that within a smaller geographic range, vector competence varied somewhat synchronously, suggesting that environmental and population genetic factors might influence vector competence. These results highlight the spatio-temporal variability in vector competence and the role of local processes.

The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans.

Mapping by admixture linkage disequilibrium (LD) detected strong association between nonmuscle myosin heavy chain 9 gene (MYH9) variants on chromosome 22 and nondiabetic nephropathy in African Americans. MYH9-related variants were posited to be the probable, but not necessarily the definitive, causal variants as a result of impressive statistical evidence of association, renal expression, and a role in autosomal dominant MYH9 disorders characterized by progressive glomerulosclerosis (Epstein and Fechtner syndromes). Dense mapping within MYH9 revealed striking LD patterns and racial variation in risk allele frequencies, suggesting population genetic factors such as selection may be operative in this region. Genovese and colleagues examined large chromosomal regions adjacent to MYH9 using genome-wide association methods and non-HapMap single nucleotide polymorphisms identified in Yoruba from the 1000 Genomes project. Statistically stronger associations were detected between two independent sequence variants in the Apolipoprotein L1 gene (APOL1) and nondiabetic nephropathy in African Americans, with odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. These kidney disease risk variants likely rose to high frequency in Africa because they confer resistance to trypanosomal infection and protect from African sleeping sickness. Risk variants in MYH9 and APOL1 are in strong LD, and the genetic risk that was previously attributed to MYH9 may reside, in part or in whole, in APOL1, although more complex models of risk cannot be excluded. This association likely explains racial disparities in nondiabetic nephropathy as a result of the high prevalence of risk alleles in individuals of African ancestry.

Heredity, diet and lifestyle as determining risk factors for the esophageal cancer on Nanao Island in Southern China

In this case-control study we evaluated contribution of environmental and genetic factors for risk of esophageal cancer (EC) by studying populations on Nanao Island (highest risk area for EC in China) and Shanwei (low risk region). Data on lifestyle, diet and family history were collected from the 166 newly diagnosed EC patients on Nanao between 2003 and 2004, from their 1450 first degree relatives and from controls on Nanao and Shanwei. Univariate and logistic regression analysis, family aggregation patterns, standardized incidence ratio (SIR), segregation ratio and heritability index were evaluated. The family cancer history was a significant risk factor for the two scenarios; Nanao cases versus Nanao controls, and Nanao controls versus Shanwei controls. Other risk factors included smoking, alcohol and fermented fish sauce. After adjusting for confounding variables, family history was independently associated with the occurrence of EC in Nanao cases versus Nanao controls. The incidence in the first degree relatives of Nanao cases was 0.86%, significantly higher than that of the public (0.12%) and SIR value was 1.44 in the first degree relatives of the 166 EC cases. The segregation ratio was 0.11 and the heritability index among first degree relatives was 40%. Our study indicates that there are steady pathogenic risk factors in the Nanao population's lifestyle but genetic factors also play an important role for EC onset.