Isolation and characterization of a highly polymorphic human locus (DXS455) in proximal Xq28

Human Xq28 is highly gene dense with over 27 loci. Because most of these genes have been mapped by linkage to polymorphic loci, only one of which (DXS52) is informative in most families, a search was conducted for new, highly polymorphic Xq28 markers. From a cosmid library constructed using a somatic cell hybrid containing human Xq27.3----qter as the sole human DNA, a human-insert cosmid (c346) was identified and found to reveal variation on Southern blot analyses with female DNA digested with any of several different restriction endonucleases. Two subclones of c346, p346.8 and p346.T, that respectively identify a multiallelic VNTR locus and a frequent two-allele TaqI polymorphism were isolated. Examination of 21 unrelated females showed heterozygosity of 76 and 57%, respectively. These two markers appeared to be in linkage equilibrium, and a combined analysis revealed heterozygosity in 91% of unrelated females. Families segregating the fragile X syndrome with key Xq28 crossovers position this locus (designated DXS455) between the proximal Xq28 locus DXS296 (VK21) and the more distal locus DXS374 (1A1), which is proximal to DXS52. DXS455 is therefore the most polymorphic locus identified in Xq28 and will be useful in the genetic analysis of this gene dense region, including the diagnosis of nearby genetic disease loci by linkage.     

Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica

We report a comparative genetic characterization of two population isolates with parallel demographic histories: the Central Valley of Costa Rica (CVCR) and Antioquia (in northwest Colombia). The analysis of mtDNA, Y-chromosome and autosomal polymorphisms shows that Antioquia and the CVCR are genetically very similar, indicating that closely related parental populations founded these two isolates. In both populations, the male ancestry is predominantly European, whereas the female ancestry is mostly Amerind. In agreement with their isolation, the Amerindian mtDNA diversity of Antioquia and the CVCR is typical of ethnically-defined native populations and is markedly lower than in other Latin American populations. A comparison of linkage disequilibrium (LD) at 18 marker pairs in Antioquia and the CVCR shows that markers in LD in both populations are located at short genetic distances (相似文献   

Neurocognitive phenotypes and genetic dissection of disorders of brain and behavior

Elucidating the molecular mechanisms underlying quantitative neurocognitive phenotypes will further our understanding of the brain's structural and functional architecture and advance the diagnosis and treatment of the psychiatric disorders that these traits underlie. Although many neurocognitive traits are highly heritable, little progress has been made in identifying genetic variants unequivocally associated with these phenotypes. A major obstacle to such progress is the difficulty in identifying heritable neurocognitive measures that are precisely defined and systematically assessed and represent unambiguous mental constructs, yet are also amenable to the high-throughput phenotyping necessary to obtain adequate power for genetic association studies. In this perspective we compare the current status of genetic investigations of neurocognitive phenotypes to that of other categories of biomedically relevant traits and suggest strategies for genetically dissecting traits that may underlie disorders of brain and behavior.     

The static allometry of sexual and nonsexual traits in vervet monkeys

Sexual traits vary tremendously in static allometry. This variation may be explained in part by body size‐related differences in the strength of selection. We tested this hypothesis in two populations of vervet monkeys, using estimates of the level of condition dependence for different morphological traits as a proxy for body size‐related variation in the strength of selection. In support of the hypothesis, we found that the steepness of allometric slopes increased with the level of condition dependence. One trait of particular interest, the penis, had shallow allometric slopes and low levels of condition dependence, in agreement with one of the most consistent patterns yet detected in the study of allometry, namely that of genitalia exhibiting shallow allometries. © 2014 The Linnean Society of London, Biological Journal of the Linnean Society, 2015, 114 , 527–537.     

Linkage disequilibrium and haplotype homozygosity in population samples genotyped at a high marker density

OBJECTIVE: Analyze the information contained in homozygous haplotypes detected with high density genotyping. METHODS: We analyze the genotypes of approximately 2,500 markers on chr 22 in 12 population samples, each including 200 individuals. We develop a measure of disequilibrium based on haplotype homozygosity and an algorithm to identify genomic segments characterized by non-random homozygosity (NRH), taking into account allele frequencies, missing data, genotyping error, and linkage disequilibrium. RESULTS: We show how our measure of linkage disequilibrium based on homozygosity leads to results comparable to those of R(2), as well as the importance of correcting for small sample variation when evaluating D'. We observe that the regions that harbor NRH segments tend to be consistent across populations, are gene rich, and are characterized by lower recombination. CONCLUSIONS: It is crucial to take into account LD patterns when interpreting long stretches of homozygous markers.     

Endophenotypes for psychiatric disorders: ready for primetime?

It is increasingly accepted that the imprecision of categorical psychiatric diagnoses can be a limiting factor in understanding the genetic basis of human behavioral abnormalities. Genetic investigation of endophenotypes--more precisely defined quantitative traits hypothesized to underlie disease syndromes--offers great promise as an alternative or complement to studies of categorical disease phenotypes. However, there is not yet standardization of the methods by which candidate endophenotypes should be chosen and applied. Fruitful endophenotype studies depend on the selection of heritable, quantitative traits that can be objectively and reliably measured. In this article, we propose guidelines for such investigations for psychiatric disorders, using endophenotypes previously proposed for bipolar disorder as particular examples. Gene expression studies and non-human primate models are recent developments in which an endophenotype approach might prove particularly valuable.     

The Genome-wide Patterns of Variation Expose Significant Substructure in a Founder Population

Although high-density SNP genotyping platforms generate a momentum for detailed genome-wide association (GWA) studies, an offshoot is a new insight into population genetics. Here, we present an example in one of the best-known founder populations by scrutinizing ten distinct Finnish early- and late-settlement subpopulations. By determining genetic distances, homozygosity, and patterns of linkage disequilibrium, we demonstrate that population substructure, and even individual ancestry, is detectable at a very high resolution and supports the concept of multiple historical bottlenecks resulting from consecutive founder effects. Given that genetic studies are currently aiming at identifying smaller and smaller genetic effects, recognizing and controlling for population substructure even at this fine level becomes imperative to avoid confounding and spurious associations. This study provides an example of the power of GWA data sets to demonstrate stratification caused by population history even within a seemingly homogeneous population, like the Finns. Further, the results provide interesting lessons concerning the impact of population history on the genome landscape of humans, as well as approaches to identify rare variants enriched in these subpopulations.     

Replication slippage may cause parallel evolution in the secondary structures of mitochondrial transfer RNAs

Presence of the dihydrouridine (D) stem in the mitochondrial cysteine tRNA is unusually variable among lepidosaurian reptiles. Phylogenetic and comparative analyses of cysteine tRNA gene sequences identify eight parallel losses of the D-stem, resulting in D-arm replacement loops. Sampling within the monophyletic Acrodonta provides no evidence for reversal. Slipped-strand mispairing of noncontiguous repeated sequences during replication or direct replication slippage can explain repeats observed within cysteine tRNAs that contain a D-arm replacement loop. These two mechanisms involving replication slippage can account for the loss of the cysteine tRNA D-stem in several lepidosaurian lineages, and may represent general mechanisms by which the secondary structures of mitochondrial tRNAs are altered.      

Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.

Progressive familial intrahepatic cholestasis (PFIC; OMIM 211600) is the second most common familial cholestatic syndrome presenting in infancy. A locus has previously been mapped to chromosome 18q21-22 in the original Byler pedigree. This chromosomal region also harbors the locus for benign recurrent intrahepatic cholestasis (BRIC) a related phenotype. Linkage analysis in six consanguineous PFIC pedigrees from the Middle East has previously excluded linkage to chromosome 18q21-22, indicating the existence of locus heterogeneity within the PFIC phenotype. By use of homozygosity mapping and a genome scan in these pedigrees, a locus designated "PFIC2" has been mapped to chromosome 2q24. A maximum LOD score of 8.5 was obtained in the interval between marker loci D2S306 and D2S124, with all families linked.