Non-pseudoautosomal Region Research Articles

Major sex differences in allele frequencies for X chromosomal variants in both the 1000 Genomes Project and gnomAD.

An unexpectedly high proportion of SNPs on the X chromosome in the 1000 Genomes Project phase 3 data were identified with significant sex differences in minor allele frequencies (sdMAF). sdMAF persisted for many of these SNPs in the recently released high coverage whole genome sequence of the 1000 Genomes Project that was aligned to GRCh38, and it was consistent between the five super-populations. Among the 245,825 common (MAF>5%) biallelic X-chromosomal SNPs in the phase 3 data presumed to be of high quality, 2,039 have genome-wide significant sdMAF (p-value <5e-8). sdMAF varied by location: non-pseudo-autosomal region (NPR) = 0.83%, pseudo-autosomal regions (PAR1) = 0.29%, PAR2 = 13.1%, and X-transposed region (XTR)/PAR3 = 0.85% of SNPs had sdMAF, and they were clustered at the NPR-PAR boundaries, among others. sdMAF at the NPR-PAR boundaries are biologically expected due to sex-linkage, but have generally been ignored in association studies. For comparison, similar analyses found only 6, 1 and 0 SNPs with significant sdMAF on chromosomes 1, 7 and 22, respectively. Similar sdMAF results for the X chromosome were obtained from the high coverage whole genome sequence data from gnomAD V 3.1.2 for both the non-Finnish European and African/African American samples. Future X chromosome analyses need to take sdMAF into account.

ROHMM-A flexible hidden Markov model framework to detect runs of homozygosity from genotyping data.

Runs of long homozygous (ROH) stretches are considered to be the result of consanguinity and usually contain recessive deleterious disease-causing mutations. Several algorithms have been developed to detect ROHs. Here, we developed a simplealternative strategy by examining X chromosome non-pseudoautosomal region to detect the ROHs from next-generation sequencing data utilizing the genotype probabilities and the hidden Markov model algorithm as a tool, namely ROHMM. It is implemented purely in java and contains both a command line and a graphical user interface. We tested ROHMM on simulated data as well as real population data from the 1000G Project and a clinical sample. Our results have shown that ROHMM can perform robustly producing highly accurate homozygosity estimations under all conditions thereby meeting and even exceeding the performance of its natural competitors.

Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias.

There is a striking and unexplained male predominance across many cancer types. A subset of X chromosome (chrX) genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative “Escape from X-Inactivation Tumor Suppressor” (EXITS) genes, we compared somatic alterations from >4100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) chrX genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) more frequently harbored loss-of-function mutations in males (based on false discovery rate <0.1), compared to zero of 18,055 autosomal and PAR genes (P<0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence compared to males across a variety of tumor types.

A map of the human genome in linkage disequilibrium units.

Two genetic maps with additive distances contribute information about recombination patterns, recombinogenic sequences, and discovery of genes affecting a particular phenotype. Recombination is measured in morgans (w) over a single generation in a linkage map but may cover thousands of generations in a linkage disequilibrium (LD) map measured in LD units (LDU). We used a subset of single nucleotide polymorphisms from the HapMap Project to create a genome-wide map in LDU. Recombination accounts for 96.8% of the LDU variance in chromosome arms and 92.4% in their deciles. However, deeper analysis shows that LDU/w, an estimate of the effective bottleneck time (t), is significantly variable among chromosome arms because (i) the linkage map is approximated from the Haldane function, then adjusted toward the Kosambi function that is more accurate but still exaggerates w for all chromosomes, especially shorter ones; (ii) the non-pseudoautosomal region of the X chromosome is subject to hemizygous selection; and (iii) at resolution less than approximately 40,000 markers per w, there are indeterminacies (holes) in the LD map reflecting intervals of very high recombination. Selection and stochastic variation in small regions must have effects, which remain to be investigated by comparisons among populations. These considerations suggest an optimal strategy to eliminate holes quickly, greatly enhance the resolution of sex-specific linkage maps, and maximize the gain in association mapping by using LD maps.

Y-Chromosome Haplotypes for Six Short Tandem Repeats (STRs) in a Mexican Population

Background Short tandem repeats (STRs) on the non-pseudoautosomal region of the Y-chromosome are DNA polymorphic markers able to solve special cases in legal medicine, for instance in paternity testing where the alleged father is not available, and in forensic situations, such as rape cases, where mixtures of male/female DNA are present. Methods Six STR polymorphisms from the Y-chromosome (DYS19, DYS385, DYS389/I, DYS390, DYS391, and DYS393) were PCR-typed in 120 males from the northwest region of Mexico by means of native polyacrylamide gel electrophoresis and silver staining. Results Allele frequencies were estimated for each STR. Their gene diversity ranged from 51.4% for DYS393 to 92.5% for DYS385. Mexican Y-STR allele distributions displayed similarity ( p >0.05) with previously reported U.S. Hispanics for DYS19, DYS389/I, DYS390, DYS391, and DYS393. Although Mexicans showed the same modal allele for DYS385 (11/14; 24.4%) with regard to most European populations, differences in allele distributions were observed ( p <0.01). The haplotype diversity and the male discriminatory capacity of this six-locus system were 99.3 and 84.1%, respectively. Conclusions This knowledge permits the effective use of these six Y-chromosome markers in legal medicine casework in the studied population. This STR-system offers a great potential to identify males and male-lineages, and can be used confidentially in paternity testing and forensic analysis in the Mexican population.

Spatial ability of XY sex-reversed female mice

Perinatal gonadal hormones significantly affect subsequent sex differences in reproductive and non-reproductive behaviors in rodents. However, the influence of the sex chromosomes on these behaviors has been largely ignored. To assess the influence of the non-pseudoautosomal region of the Y chromosome, C57BL/JEi male and female mice and mice from the C57BL/6JEi-Y POS consomic strain were given behavioral tests known to distinguish males from females. The C57BL/6JEi-Y POS strain contains sex-reversed XY-females which, when compared to their XX-female siblings, allow assessment of the influence of the Y chromosome in a female phenotype. XX-females and XY-females did not differ on open-field activity, the Lashley maze, or active avoidance learning, but XY-females were significantly better than XX-females on the Morris hidden platform spatial maze. These findings suggest that males may have both a genetic and a hormonal mechanism to ensure visuospatial superiority.

Effects of the non-pseudoautosomal region of the Y-chromosome on behavior in female offspring of two congenic strains of mice

The learning behavior of female offspring of two strains of mice congenic for the Y-chromosome, BXSX/MpJ-Yaa and BXSB/MpJ-Yaa+, was examined. Significant differences were found in the Morris water maze and the Lashley III maze, demonstrating that the fathers' Y-chromosome can indirectly affect their daughters' behavior. Approximately half the mice had neocortical ectopias, and females from the two paternal groups reacted differently to the presence or absence of ectopias. Since females do not have a Y-chromosome, these effects must be through non-genetic mechanisms. Prenatal factors that could have played a role include possible differences in gonadal growth and the presence of different H-Y antigens. Postnatally, the sires and male siblings of the two strains may not have behaved the same toward the female offspring and/or the dams, creating differences in behavior. In summary, the behavior of female offspring of two groups of males, genetically the same except for their Y-chromosomes, was examined. Since females do not receive a Y-chromosome from their fathers, in theory their behavior should not differ. Significant differences were found, indicating that the Y-chromosome, through some indirect mechanism, can affect females of the next generation.

Radial maze learning in two inbred mouse strains and their reciprocal congenics for the non-pseudoautosomal region of the Y chromosome

The effect of the non-pseudoautosomal region of the Y chromosome on spatial learning in a radial maze task was examined in two inbred mouse strains, NZB and CBA/H, and their respective congenics for the Y NPAR . Seven variables reflecting learning performance, learning strategy and lateralisation were measured. We found no substantial effect of the Y NPAR on radial maze learning, but modest influences on behavioral strategies. These findings are in agreement with previous results regarding the sizes of the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields.

Can we escape our genetic destiny?

During 1998, progress has been made in the identification of specific genes that are responsible for, or predispose to, endocrine disorders. Several genetic abnormalities of the thyroid have been described, such as two new mutations in exon 10 of the thyrotropin-receptor gene, resulting in a clinical picture of thyroid hypoplasia and congenital hypothyroidism as well as germ-line neo-mutations in the extracellular portion of the thyrotropin receptor, leading to an opposite clinical picture of severe congenital hyperthyroidism. In addition to previously disovered mutations, new mutations in the PIT-I and the PROP-I gene, responsible for combined pituitary hormone deficiency, have been reported. In patients with septo-optic dysplasia a mutation in the homeobox gene HESXI/Hesxl was found, indicating that the gene plays an important role in the development of Will the forebrain, midline, and pituitary. Growth hormone insensitivity syndrome (GHIS) is now associated with'a broad spectrum of mutations of the GH receptor gene. Woods and colleagues showed that GHIS is, a highly variable condition--from severely affected patients with classical GH insensitivity to a larger group of with idiopathic short stature. Other genetic and/or environmental factors must, therefore, contribute to the phenotype. Intriguing results were found when families with LeriWeill dyschondrosteosis (LWD), a dominant inherited skeletal dysplasia characterised by disproportionate short stature with mesomelic limb shortening, were studied. Various mutations of the short stature homeoboxcontaining gene (SHOX) were found in patients with LWD. These S H O X mutations, however, have also been found in idiopathic growth retardation and Turner (XO) short stature, conditions without bone dysplasia. One explanation is that loss of other genes from the nonpseudoautosomal region of the X chromosome in Turner 's syndrome may mask the full phenotype of S H O X haploinsufficiency. The variable expression in families segretating for a S H O X deletion or mutation suggests that there may be a modifying gene, or genes, on an autosome or on the X chromosome itself, and background genetic effects and environmental factors may also play a role. The mentioned genetic disorders are just examples. Reports about various mutations have appeared in 1998, indicating that in the coming, years many endocrine disorders will be found to be genetically determined. Research in the field of obesity and leptin has progressed. In a large population of massively obese people, however, no mutations of the leptin receptor were found. Feeding behaviour and caloric balance are also modified by neuronal effectors such as neuropeptide Y,

Intermale aggression, GAD activity in the olfactory bulbs and Y chromosome effect in seven inbred mouse strains

The capacity to attack a passive standard opponent in a resident-intruder test and the GAD activity in the olfactory bulbs were measured in 140 male mice from seven different inbred mouse strains. The effect of the non-pseudo autosomal region of the Y-chromosome (Y NPAR ) on these two phenotypes has also been investigated using a quartet of reciprocal strains congenic for the Y NPAR . A strong negative correlation was found between the two variables but the Y NPAR is not involved. This result suggests that males of more attacking strains have a lower olfactory threshold, making the olfactory discrimination of the opponent easier and its identification as a stranger more efficient.

Comparative cytogenetic mapping reveals chromosome rearrangements between the X chromosomes of two closely related mammalian species (cattle and goats)

Cytogenetic localization of 24 BACs containing type I (genes and ESTs) and type II (microsatellites) markers were used to construct cytogenetic maps of caprine (CHI) and bovine (BTA) X chromosomes. Comparison of these two maps revealed that the distal region of the goat X long arm (CHI Xq38→q42) was located inside the bovine X chromosome, between PGK1 (BTA Xq25) and DVEPC137 (BTA Xq12). The marker order was globally conserved without any pericentric inversion, as previously postulated in the literature. The caprine centromere was found between DVEPC053 and DVEPC102 (belonging to the same band in the bovine X: BTA Xq41), whereas the bovine centromere was between DVEPC076 and DVEPC132, belonging to the same region of the caprine X chromosome (CHI Xq31→q33). The pseudoautosomal region was situated at the tip of the bovine X long arm and on the tiny short arm of the caprine X chromosome. In the non-pseudoautosomal (NPA) region, the synteny of coding sequences was well conserved between the human species and the two ruminant species, but the gene order was dramatically divergent. It is suggested that the 24 BACs of this study could constitute a new tool to measure phylogenetic distances between different mammalian species by comparing chromosome rearrangements inside the NPA region of the X.

Searching for candidate genes with effects on an agonistic behavior, offense, in mice.

It is well established that the agonistic behavior of offense in mice is heritable. However, few genes have been identified or mapped for offense. For segments of chromosomes with effects on offense, a positional candidate strategy can be used to find such genes. This approach is illustrated for the effect of the male specific part (nonpseudoautosomal region; NPAR) of the mouse Y chromosome on offense. It is proposed that a positional candidate for this effect is Sry. The Sry protein is a transcription factor. Its mRNA is expressed in fetal and adult brain. Its protein binds to response elements in the 5' end of the aromatase and the Fra1 genes. Each of these genes has potential effects on several brain neurotransmitter systems involved in offense. The NPAR Y chromosomes of several pairs of inbred strains have differential effects on offense. This hypothesis would be tested by sequencing Sry for some of these pairs of strains.

Aggression in wild house mice: current state of affairs.

This paper reviews our present state of knowledge of genetic variation in (offensive) aggression in wild house mice. The basic tools in this research were lines bidirectionally selected for attack latency (fast attacking SAL and slow attacking LAL males), descended from a feral population. Using congenic lines for the nonpseudoautosomal region of the Y chromosome (YNPAR), reciprocal crosses between (parental) SAL and LAL, and crosses between parentals and congenics, an autosomally dependent Y chromosomal effect on aggression has been found. Both the pseudoautosomal (YPAK) region and the YNPAR play a role. As for environmental sources of variation, prenatal and postnatal maternal effects are of minor importance for the development of aggression differences. One of the physiological factors by which genetic effects may be mediated is testosterone (T). Besides quantitative aspects, the timing of T release seems crucial. Two important time frames are discussed: the perinatal and pubertal time periods. Finally, neurochemical and neuroanatomical correlates are considered. Differences in neostriatal dopaminergic activity, and sizes of the intra- and infrapyramidal mossy fiber terminal fields, as well as Y chromosomal effects on the latter two, are discussed.

Hippocampal morphology in the inbred mouse strains NZB and CBA/H and their reciprocal congenics for the nonpseudoautosomal region of the Y chromosome

The effects of the nonpseudoautosomal region of the Y chromosome (YNPAR) on hippocampal morphology have been investigated in the inbred mouse strains NZB/BINJ and CBA/H, using comparisons between the two parentals and their respective congenics N.H-YNPAR and H.N-YNPAR. Results obtained depend upon the hippocampal variable measured. YNPAR had no effect on the sizes of the stratum oriens, hilus, or mossy fiber terminal fields (both suprapyramidal and intra- and infrapyramidal). However, in interaction with the strain background, it affected the strata lacunosum-moleculare, radiatum, and pyramidale. Possible relationships among gene(s), mossy fiber terminal fields, and intermale aggression are discussed.

Intermale aggression tested in two procedures, using four inbred strains of mice and their reciprocal congenics: Y chromosomal implications.

Indications of a role for the nonpseudoautosomal region of the Y chromosome (YNPAR) in intermale attack behavior have been demonstrated by Maxson's group using C57BL/10 (B10) and DBA/1 (D1) inbred mouse strains and their reciprocal congenics. Carlier and Roubertoux' group, using CBA/H (H) and NZB/B1NJ (N) mice, did not find such a YNPAR effect. For the two research groups, however, not only were the parental strains different, but also the rearing conditions and testing methods. The divergent conclusions drawn may therefore have been due either to genetic variation or to environment-related variables. We carried out two experiments to investigate these alternatives. The N and H strains were raised and tested according to the experimental design used by Maxson's group (homogeneous set test) and the D1 and B10 strains were raised and tested according to the experimental design of Carlier and Roubertoux' group (standard opponent test). Considering all studies together, the YNPAR effect appeared in both sets of mice only when using the homogeneous set test. This raises the question of what environmentally related variables are involved in the YNPAR effect on intermale attack. One strong hypothesis is that the different types of opponents in each experimental design send differing olfactory signals, which, in turn, differentially affect the capacity to elicit intermale attack behavior.

Y chromosomal effects on hippocampal mossy fiber distributions in mice selected for aggression

The influence of the non-pseudoautosomal region of the Y chromosome (Y NPAR ) on the sizes of the hippocampal intra- and infrapyramidal mossy fiber (IIPMF) terminal fields was examined in wild house mice. For this purpose selection lines for short attack latency (SAL), long attack latency (LAL), and their respective congenics for the Y NPAR were used. We found an incremental effect of the (non-aggressive) LAL Y NPAR , combined with an additive effect of the line background on the sizes of the IIPMF terminal fields. In contrast, only the line background affected attack latency. The implications of this finding for the previously observed correlation between the size of the IIPMF and aggression in male house mice are discussed.

Co-segregation of intermale aggression with the pseudoautosomal region of the Y chromosome in mice.

The sexual dimorphism of aggression has led to a search for its Y chromosomal correlates. We have previously confirmed that initiation of attack behavior against a conspecific male is Y-dependent in two strains of laboratory mice (NZB and CBA/H). We provide evidence that the non-pseudoautosomal region of the Y is not involved and that only the pseudoautosomal region of the Y is correlated with initiation of attack behavior. The autosomal correlates also contribute to this behavior in an additive or interactive manner with the pseudoautosomal correlates.

Olfactory discrimination of urinary odortypes from congenic strains (DBA/1Bg and DBA1.C57BL10-YBg) of mice differing in their Y chromosomes.

Differential effects of one or more genes in the nonpseudoautosomal region of the DBA1 and C57BL10 Y chromosomes on offensive attack may be mediated, at least in part, by differential effects of this Y chromosomal gene(s) on the sending and receiving of discriminable urinary odortypes. This hypothesis is based, in part, on the report that urine from a pair of Y chromosomal congenic strains (C57BL6.AKR-Y and C57BL6) of mice can be discriminated in a Y maze test. The AKR and C57BL6 Y chromosomes come from two distinct species of mouse (Mus domesticus and Mus musculus, respectively). Thus, this Y chromosomal variant exists between mouse species. The DBA1 and C57BL10 Y chromosomes come from a single species, Mus musculus. Here we show that in the Y maze system previously used, urine from mice with the DBA1 and with the C57BL10 Y chromosomes can also be discriminated. Thus, there are discriminable urinary odortypes for this pair of Y chromosomes from the same species, Mus musculus.