Associations between maternal prenatal stress, methylation changes in IGF1 and IGF2, and birth weight.

Maternal stress has been linked to low birth weight in newborns. One potential pathway involves epigenetic changes at candidate genes that may mediate the effects of prenatal maternal stress on birth weight. This relationship has been documented in stress-related genes, such as NR3C1. There is less literature exploring the effect of stress on growth-related genes. IGF1 and IGF2 have been implicated in fetal growth and development, though via different mechanisms as IGF2 is under imprinting control. In this study, we tested for associations between prenatal stress, methylation of IGF1 and IGF2, and birth weight. A total of 24 mother-newborn dyads in the Democratic Republic of Congo were enrolled. Ethnographic interviews were conducted with mothers at delivery to gather culturally relevant war-related and chronic stressors. DNA methylation data were generated from maternal venous, cord blood and placental tissue samples. Multivariate regressions were used to test for associations between stress measures, DNA methylation and birth weight in each of the three tissue types. We found an association between IGF2 methylation in maternal blood and birth weight. Previous literature on the relationship between IGF2 methylation and birth weight has focused on methylation at known differentially methylated regions in cord blood or placental samples. Our findings indicate there may be links between the maternal epigenome and low birth weight that rely on mechanisms outside known imprinting pathways. It thus may be important to consider the effect of maternal exposures and epigenetic profiles on birth weight even in the setting of maternally imprinted genes such as IGF2.

Effect of different sampling strategies for a single geographic region in Yemen on standard genetic analyses of mitochondrial DNA sequence data.

Collection of biological samples is the foundation of genetic studies ranging from estimation of genetic diversity to reconstruction of population history. Sample collections are intended to accurately represent the genetic, biological, ecological, cultural, geographic, and/or linguistic diversity of a particular region or population by providing a small, but representative, set of samples. In this study, we analyze human mitochondrial DNA variation in samples collected using four different sampling strategies to represent the same geographic region. Specifically, samples were collected from a village, a rural area, a regional clinic, and a national university in the governorate of Dhamar in Yemen. All samples were assayed for mitochondrial hypervariable region I DNA sequence variation and data were subjected to standard molecular genetic analyses. Our results suggest that analyses in which individual DNA sequences are explicitly compared or evaluated, e.g. phylogenetic and network analyses, may be more sensitive to sample collection design than analyses in which data are averaged across individuals or are analyzed more indirectly, e.g. summary statistics.

Allelic variation and haplotype structure of the dopamine receptor gene DRD2 in nine Indian populations.

The human dopaminergic system is a significant focal point of study in the fields of neuropsychiatry and pharmacology, plus it is also a promising nuclear DNA marker in studies of human genome diversity. In this study, we assayed six polymorphic markers in the dopamine D2 receptor gene (DRD2) in 482 unrelated individuals from nine ethnic populations of India. Our results demonstrate that the six markers are highly polymorphic in all populations and the constructed haplotypes show a high level of heterozygosity. Out of the eight possible three-site haplotypes, all populations commonly shared only three haplotypes. The haplotypes exhibited fairly high frequencies across multiple populations; Kurumba population showed all eight three-site haplotypes. The ancestral haplotype (B2-D2-Al) was observed at high frequency only in the Siddi population. Haplotypes based on all six markers revealed 16 haplotypes, out of which only 6 are most common with a frequency of greater than 5% in at least one of the nine populations. But only three haplotypes were shared by all nine populations with the cumulative frequency ranging from 80.8% (Kurumba) to 96.6% (Onge). Great variation in levels of linkage disequilibrium (LD) was detected, ranging from complete LD in the Badaga to virtually no LD in the Siddi. This range of LD likely reflects different population histories, such as African ancestry in the Siddi and recent founding events in the population isolates, Badaga and Kota.

Allelic variation in the NPY gene in 14 Indian populations.

NPY is a 36-aminoacid peptide expressed in several areas of the nervous system. Neuropeptide Y (NPY) receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. The human NPY gene is located in chromosome 7. The functional significance of coding Leu7Pro polymorphism in the signal peptide of preproNPY is known. Six hundred and fifty four individuals of 14 ethnic Indian populations were screened for three mutations in the NPY gene, including Leu7Pro. We found that the Pro7 frequencies among the studied populations were much higher than in previous studies from other parts of the world. The highest allele frequency of Pro7 was detected in the Kota population in the Nilgiri Hill region of south India, and this may reflect a founder event in the past or genetic drift. All populations followed the Hardy-Weinberg equilibrium for the assayed markers. A total of five haplotypes were observed, only two of which were found to occur with a high frequency in all populations. No linkage disequilibrium (LD) was observed across the tested alleles in any population with the exception of Leu7Pro and Ser50Ser in the Badaga population (chi(2) = 13.969; p = 0.0001).

Identification of the most informative regions of the mitochondrial genome for phylogenetic and coalescent analyses.

Analysis of complete mitochondrial genome sequences is becoming increasingly common in genetic studies. The availability of full genome datasets enables an analysis of the information content distributed throughout the mitochondrial genome in order to optimize the research design of future evolutionary studies. The goal of our study was to identify informative regions of the human mitochondrial genome using two criteria: (1) accurate reconstruction of a phylogeny and (2) consistent estimates of time to most recent common ancestor (TMRCA). We created two series of datasets by deleting individual genes of varied length and by deleting 10 equal-size fragments throughout the coding region. Phylogenies were statistically compared to the full-coding-region tree, while coalescent methods were used to estimate the TMRCA and associated credible intervals. Individual fragments important for maintaining a phylogeny similar to the full-coding-region tree encompassed bp 577-2122 and 11,399-16,023, including all or part of 12S rRNA, 16S rRNA, ND4, ND5, ND6, and cytb. The control region only tree was the most poorly resolved with the majority of the tree manifest as an unresolved polytomy. Coalescent estimates of TMRCA were less sensitive to removal of any particular fragment(s) than reconstruction of a consistent phylogeny. Overall, we discovered that half the genome, i.e., bp 3669-11,398, could be removed with no significant change in the phylogeny (p(AU)=0.077) while still maintaining overlap of TMRCA 95% credible intervals. Thus, sequencing a contiguous fragment from bp 11,399 through the control region to bp 3668 would create a dataset that optimizes the information necessary for phylogenetic and coalescent analyses and also takes advantage of the wealth of data already available on the control region.

Mitochondrial sequence diversity of the southernmost extant New World monkey, Alouatta caraya.

Variability in mitochondrial DNA sequences was analyzed in the howler monkey, Alouatta caraya, in order to delineate evolutionary relationships among populations in the most southerly distributed New World monkey. Based on new and previously published sequence data, fourteen cytochrome b haplotypes were observed among 33 howlers sampled in Argentina, Paraguay and Brazil, and grouped in two main haplogroups. In northeastern Argentina and southern Paraguay, new sequence data on 73 specimens sampled from six localities gave 34 control region haplotypes that also clustered in two main haplogroups. At this southern distribution, both mitochondrial markers revealed the presence of two sympatric and differentiated clades that we interpret to be the consequence of a secondary contact between previously allopatric populations. Given evidence for a demographic expansion at the beginning of the Holocene 15,500-7000 years ago (Fu's test, F(S)=-12.137; P<0.001), we suggest that atleast two populations of A. caraya have colonized the southernmost range since the Holocene employing forested corridors on the Paraná and Paraguay Rivers.

Genetic variation at the mitochondrial DNA 9-bp repeat locus in the Sakha of Siberia.

Genetic variation at the mitochondrial DNA 9-bp repeat locus was assayed in 779 Sakha from Siberia. Fourteen deletion (1.8%), nine triplication (1.2%), and two 4-repeat alleles (0.26%) were identified. Several of these alleles were also detected as heteroplasmies. Among the four heteroplasmic individuals identified (0.51%), three different combinations of repeat alleles were present: 1/2, 2/3, and 2/3/4 copies. Hypervariable region I (HVRI) sequencing revealed that three different sets of haplogroups were associated with the three most frequent 9-bp polymorphisms: (1) haplo-groups B, T, and W for deletions; (2) haplogroups C, D, and K for triplications; and (3) haplogroups C, D, and T for heteroplasmies. Both of the two 4-repeat alleles were associated with haplogroup D. We detected more types of 9-bp polymorphisms and more genetic variation within classes of polymorphism than previously reported for any single population. We also present the largest and most geographically diverse sampling of the Sakha population to date. No neighboring populations have been reported to carry a non-haplogroup B deletion, triplication, or heteroplasmy, suggesting that shared ancestry or admixture or both are unlikely explanations for the presence of these polymorphisms in the Sakha. The identification of high levels of variation may be a function of the large sample size and the in-depth analysis of all derived polymorphisms. Further study of the Sakha is warranted to determine whether the level of variation is unexpectedly high, especially in light of the presence of different heteroplasmies, which suggests multiple recent events.

Molecular evolution of the tprC, D, I, K, G, and J genes in the pathogenic genus Treponema.

We investigated the evolution of 6 genes from the Treponema pallidum repeat (tpr) gene family, which encode potential virulence factors and are assumed to have evolved through gene duplication and gene conversion events. The 6 loci (tprC, D, G, J, I, and K) were sequenced and analyzed in several members of the genus Treponema, including the 3 subspecies of human T. pallidum (T. pallidum subsp. pallidum, pertenue, and endemicum), Treponema paraluiscuniculi (rabbit syphilis), and the unclassified Fribourg-Blanc (simian) isolate. Phylogenetic methods, recombination analysis, and measures of nucleotide diversity were used to investigate the evolutionary history of the tpr genes. Numerous instances of gene conversion were detected by all 3 methods including both homogenizing gene conversion that involved the entire length of the sequence as well as site-specific conversions that affected smaller regions. We determined the relative age and directionality of the gene conversion events whenever possible. Our data are also relevant to a discussion of the evolution of the treponemes themselves. Higher levels of variation exist between the human subspecies than within them, supporting the classification of the human treponemes into 3 subspecies. In contrast to published theories, the divergence and diversity of T. pallidum subsp. pertenue relative to the other subspecies does not support a much older origin of yaws at the emergence of modern human, nor is the level of divergence seen in T. pallidum subsp. pallidum consistent with a very recent (< 500 years) origin of this subspecies. In general, our results demonstrate that intragenomic recombination has played a significant role in the evolution of the studied tpr genes and emphasize that efforts to infer evolutionary history of the treponemes can be complicated if past recombination events are not recognized.