Biomedical subjects

M Bamshad

Publications and source records attributed to M Bamshad.

At least 37 records · Page 2Linked to original sources

PubMed1998

Using mitochondrial and nuclear DNA markers to reconstruct human evolution.

Molecular genetic-data have greatly improved our ability to test hypotheses about human evolution. During the past decade, a large amount of nuclear and mitochondrial data have been collected from diverse human populations. Taken together, these data indicate that modern humans are a relatively young species. African populations show the largest amount of genetic diversity, and they are the most genetically divergent population. Modern human populations expanded in size first on the African continent. These findings support a recent African origin of modern humans, but this conclusion should be tempered by the possible effects of factors such as gene flow, population size differences, and natural selection.

Africa↗

PubMed1998

Role of vasopressin and oxytocin in the control of social behavior in Syrian hamsters (Mesocricetus auratus).

Vasopressin (VP) and oxytocin (OT) play an important role in regulating social behavior in a variety of species as a result of their actions in the central nervous system. The following paper reviews the actions of VP and OT in controlling a range of social behaviors involved in communication, aggression and reproduction in the Syrian hamster. These data suggest that social and hormonal stimuli alter the expression of specific social behaviors by altering the release of, or the response to, VP and OT within key elements of the neural circuits controlling these behaviors.

Animals↗

PubMed1998

Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19.

Congenital limb malformations rank behind only congenital heart disease as the most common birth defects observed in infants. Finding genes that cause defects in human limb patterning should be straightforward but has been limited, in part, by the bewildering spectrum of phenotypes, which are difficult to separate into etiologically distinct disorders. One approach to the identification of relevant genes is to take advantage of unique extended kindreds in which a defect in limb patterning is segregating. Recently, a large Dutch family with ectrodactyly, ectodermal dysplasia, cleft palate, and urogenital defects (EEC) was described by Maas et al. We have studied this kindred and localized a gene causing EEC to a locus on chromosome 19, in a region defined by D19S894 and D19S416. A second extended kindred with EEC does not map to this locus, indicating that EEC is a genetically heterogeneous disorder. Growth and patterning of the limbs, teeth, hair, and genitourinary system are mediated in part by epithelial-mesenchyme inductive interactions. The identification of both the gene causing EEC and its mutation may further elucidate the general signals mediating inductive mechanisms.

Abnormalities, Multiple↗

PubMed1998

Signatures of population expansion in microsatellite repeat data.

To examine the signature of population expansion on genetic variability at microsatellite loci, we consider a population that evolves according to the time-continuous Moran model, with growing population size and mutations that follow a general asymmetric stepwise mutation model. We present calculations of expected allele-size variance and homozygosity at a locus in such a model for several variants of growth, including stepwise, exponential, and logistic growth. These calculations in particular prove that population bottleneck followed by growth in size causes an imbalance between allele size variance and heterozygosity, characterized by the variance being transiently higher than expected under equilibrium conditions. This effect is, in a sense, analogous to that demonstrated before for the infinite allele model, where the number of alleles transiently increases after a stepwise growth of population. We analyze a set of data on tetranucleotide repeats that reveals the imbalance expected under the assumption of bottleneck followed by population growth in two out of three major racial groups. The imbalance is strongest in Asians, intermediate in Europeans, and absent in Africans. This finding is consistent with previous findings by others concerning the population expansion of modern humans, with the bottleneck event being most ancient in Africans, most recent in Asians, and intermediate in Europeans. Nevertheless, the imbalance index alone cannot reliably estimate the time of initiation of population expansion.

Genetics, Population↗

PubMed1998

Central nervous system origins of the sympathetic nervous system outflow to white adipose tissue.

White adipose tissue (WAT) is innervated by postganglionic sympathetic nervous system (SNS) neurons, suggesting that lipid mobilization could be regulated by the SNS [T. G. Youngstrom and T. J. Bartness. Am. J. Physiol. 268 (Regulatory Integrative Comp. Physiol. 37): R744-R751, 1995]. A viral transsynaptic retrograde tract tracer, the pseudorabies virus (PRV), was used to identify the origins of the SNS outflow from the brain to WAT neuroanatomically. PRV was injected into epididymal or inguinal WAT (EWAT and IWAT, respectively) of Siberian hamsters and IWAT of rats. PRV-infected neurons were visualized by immunocytochemistry and found in the spinal cord, brain stem (medulla, nucleus of the solitary tract, caudal raphe nucleus, C1 and A5 regions), midbrain (central gray), and several areas within the forebrain. The general pattern of infection of WAT in both species was more similar than different and resembled that seen after PRV injections into the adrenal medulla in rats (A. M. Strack, W. B. Sawyer, J. H. Hughes, K. B. Platt, and A. D. Loewy. Brain Res. 491: 156-162, 1989). EWAT versus IWAT injected hamsters had relatively less labeling in the suprachiasmatic, dorsomedial, and arcuate nuclei. Overall, it appeared that the SNS innervation of WAT originates from the general SNS outflow of the central nervous system and therefore may play a significant role in lipid mobilization.

Adipose Tissue↗

PubMed1998

Innervation of mammalian white adipose tissue: implications for the regulation of total body fat.

We review the extensive physiological and neuroanatomical evidence for the innervation of white adipose tissue (WAT) by the sympathetic nervous system (SNS) as well as what is known about the sensory innervation of this tissue. The SNS innervation of WAT appears to be a part of the general SNS outflow from the central nervous system, consisting of structures and connections throughout the neural axis. The innervation of WAT by the SNS could play a role in the regulation of total body fat in general, most likely plays an important role in regional differences in lipid mobilization specifically, and may have a trophic affect on WAT. The exact nature of the SNS innervation of WAT is not known but it may involve contact with adipocytes and/or their associated vasculature. We hypothesize that the SNS innervation of WAT is an important contributor to the apparent "regulation" of total body fat.

Adipose Tissue↗

PubMed1997

Microsatellite diversity and the demographic history of modern humans.

We have examined differences in diversity at 60 microsatellite loci among human population samples from three major continental groups to evaluate the hypothesis of greater African diversity in this rapidly evolving class of loci. Application of a statistical test that assumes equal mutation rates at all loci fails to demonstrate differences in microsatellite diversity, while a randomization test that does not make this assumption finds that Africans have significantly greater microsatellite diversity (P < 10(-8)) than do Asians and Europeans. Greater African diversity is most apparent at loci with smaller overall variance in allele size, suggesting that the record of population history has been erased at repeat loci with higher mutation rates. A power analysis shows that only 35-40 microsatellites are needed to establish this difference statistically, demonstrating the considerable evolutionary information contained in these systems. On average, African populations have approximately 20% greater microsatellite diversity than do Asian and European populations. A comparison of continental diversity differences in microsatellites and mtDNA sequences suggests earlier demographic expansion of the ancestors of Africans.

Africa↗

PubMed1997

Role of the central amygdala in social communication in Syrian hamsters (Mesocricetus auratus).

In Syrian hamsters, vasopressin (AVP) controls a form of scent marking called flank marking. Microinjection and lesion studies have identified several components of the neural circuit controlling this behavior. Microinjection of AVP into the medial preoptic-anterior hypothalamus (MPOA-AH), lateral septal nucleus (LS), bed nucleus of stria terminalis (BNST), and periaqueductal gray (PAG) stimulates an intense bout of flank marking. Lesions of areas such as the MPOA-AH and the LS inhibit flank marking. Other studies employing Fos immunocytochemistry suggest that the central amygdala (Ce) might be a component of this neural circuit. The purpose of the present study was to assess the significance of the Ce in regulation of AVP-induced flank marking. In Expt. 1A, the Ce of hamsters were either lesioned with ibotenic acid or sham-lesioned. In Expt. 1B, the Ce of hamsters were either lesioned electrolytically or sham-lesioned. All lesions were made bilaterally. One week later, hamsters were microinjected with AVP into the MPOA-AH and immediately tested for flank marking. In Expt. 2, the hamsters were microinjected with AVP into the Ce and were immediately tested for flank marking. Ibotenic lesions of the Ce reduced flank marking and electrolytic lesions completely inhibited flank marking in response to AVP microinjected into the MPOA-AH. Sham-lesions or lesions placed in other areas of the amygdala resulted in intense bouts of AVP-induced flank marking and flank grooming. No flank marking or flank grooming was observed in response to AVP microinjected into the Ce. These data indicate that the Ce plays a critical role in AVP-induced flank marking, although flank marking is not induced by AVP within the Ce itself.

Aggression↗

PubMed1997

Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Abnormalities, Multiple↗

PubMed1997

A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter.

Distal arthrogryposis type 1 (DA1) and Freeman-Sheldon syndrome (FSS) are the two most common known causes of inherited multiple congenital contractures. We recently have characterized a new disorder (DA2B) with a phenotype intermediate between DA1 and FSS. We report the mapping of a gene that causes DA2B to chromosome 11p15.5-pter. Linkage analysis in a single kindred generated a positive LOD score of 5.31 at theta = 0 with the marker D11S922, and recombinants localize the gene to an approximately 3.5-6.5-cM region between the marker TH and the telomere. Analysis of additional families improves the LOD score to 6.45 at theta = 0 and suggests linkage homogeneity for DA2B.

Abnormalities, Multiple↗

PubMed1996

A revised and extended classification of the distal arthrogryposes.

Since the group of disorders known as the distal arthrogryposes (DAs) were defined, additional disorders characterized by multiple congenital contractures of the distal limbs were described, and the distribution of phenotypic findings in the DAs has been expanded. The breadth of disorders labeled as DAs has diminished the usefulness of the DA classification. We propose a strict definition of DA and diagnostic criteria for DA disorders. Subsequently, we use these standards and propose a revised classification of discrete conditions that should be labeled DAs. Optimally, this serves as a framework for a DA classification based on underlying molecular and physiologic abnormalities.

Arthrogryposis↗

PubMed1996

Distal arthrogryposis type 1: clinical analysis of a large kindred.

We describe the clinical findings of 15 individuals in a large kindred affected with distal arthrogryposis type 1A (DA1A). The most consistent findings among individuals were overlapping fingers at birth, abnormal digital flexion creases, and foot deformities, including talipes equinovarus and vertical talus. There was marked intrafamilial variation in the expression of DA1A. Linkage mapping of the locus for DA1A suggests that the use of strict diagnostic criteria excludes unaffected individuals rigorously, but can produce incomplete ascertainment of affected individuals. In the context of an affected family, the range of phenotypes consistent with a diagnosis of DA1A needs to be expanded.

Arthrogryposis↗

PubMed1996

Clinical analysis of a large kindred with the Pallister ulnar-mammary syndrome.

The ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies. We present the clinical descriptions of 33 members of a six generation kindred with UMS. The number of affected individuals in this family is more than the sum of all previously reported cases of UMS. The clinical expression of UMS is highly variable. While most patients have limb deficiencies, the range of abnormalities extends from hypoplasia of the terminal phalanx of the 5th digit to complete absence of the ulna and 3rd, 4th, and 5th digits. Moreover, affected individuals may have posterior digital duplications with or without contralateral limb deficiencies. Apocrine gland abnormalities range from diminished axillary perspiration with normal breast development and lactation, to complete absence of the breasts and no axillary perspiration. Dental abnormalities include misplaced or absent teeth. Affected males consistently undergo delayed puberty, and both sexes have diminished to absent axillary hair. Imperforate hymen were seen in some affected women. A gene for UMS was mapped to chromosome area 12q23-q24.1. A mutation in the gene causing UMS can interfere with limb patterning in the proximal/distal, anterior/posterior, and dorsal/ventral axes. This mutation disturbs development of the posterior elements of forearm, wrist, and hand while growth and development of the anterior elements remain normal.

Abnormalities, Multiple↗

PubMed1996

Glutamate and vasopressin interact to control scent marking in Syrian hamsters (Mesocricetus auratus).

In Syrian hamsters, vasopressin (AVP) in the medial preoptic-anterior hypothalamus (MPOA-AH) controls a form of scent marking called flank marking. Another neurochemical signal that may interact with AVP to control flank marking is glutamate. We tested the hypothesis that glutamate interacts with AVP in the MPOA-AH to regulate flank marking. On day 1, AVP was microinjected into the MPOA-AH. On day 2, AVP was microinjected as a cocktail combining either AP-5, a NMDA antagonist, or GAMS, a non-NMDA antagonist or propranolol, a beta norepinephrine antagonist. On day 3, AVP alone was microinjected. Hamsters engaged in high levels of marking in response to AVP alone or to a combination of AVP and propranolol. In contrast, the frequency of marking was significantly reduced in response to a combination of either AVP and AP-5 or AVP and GAMS. These data support the hypothesis that stimulation of flank marking by AVP within the MPOA-AH requires the activity of glutamate.

2-Amino-5-phosphonovalerate↗

PubMed1996

Neural circuitry controlling vasopressin-stimulated scent marking in Syrian hamsters (Mesocricetus auratus).

In Syrian hamsters, arginine vasopressin (AVP) plays a critical role in the control of a form of scent marking called flank marking. Microinjection of AVP into the medial preoptic-anterior hypothalamus (MPOA-AH), lateral septal nucleus (LS), bed nucleus of the stria terminalis (BNST), and the periaqueductal gray (PAG) stimulates high levels of flank marking. Microinjection of an antagonist of the V1a-AVP receptor into sites such as the MPOA-AH inhibits expression of flank marking. The purpose of the present study was to investigate the neural circuit controlling flank marking by localizing the induction of Fos protein in response to the microinjection of AVP, a V1a-AVP antagonist (AVPA) or saline into the MPOA-AH. Immediately after microinjection, hamsters were placed in a clean cage and their behavior was videotaped for 10 minutes. Ninety minutes after the behavioral experiment hamsters were perfused and their brains removed for subsequent immunocytochemical localization of Fos protein. The number of Fos-positive neurons was significantly greater in the BNST, PAG, and central amygdala (Ce) following the microinjection of AVP than following the microinjection of either AVPA or saline. In AVP-injected animals, the number of Fos-labeled cells in the Ce, PVN, and PAG increased with increased frequency of either flank marking or flank gland grooming. These data support the hypothesis that neurons within the MPOA-AH, BNST, and PAG play an important role in the control of flank marking and suggest that the Ce may be a previously unrecognized part of this neural circuit.

Amygdala↗

PubMed1996

mtDNA variation in caste populations of Andhra Pradesh, India.

Various anthropological analyses have documented extensive regional variation among populations on the subcontinent of India using morphological, protein, blood group, and nuclear DNA polymorphisms. These patterns are the product of complex population structure (genetic drift, gene flow) and a population history noted for numerous branching events. As a result, the interpretation of relationships among caste populations of South India and between Indians and continental populations remains controversial. The Hindu caste system is a general model of genetic differentiation among endogamous populations stratified by social forces (e.g., religion and occupation). The mitochondrial DNA (mtDNA) molecule has unique properties that facilitate the exploration of population structure. We analyzed 36 Hindu men born in Andhra Pradesh who were unrelated matrilineally through at least 3 generations and who represent 4 caste populations: Brahmin (9), Yadava (10), Kapu (7), and Relli (10). Individuals from Africa (36), Asia (36), and Europe (36) were sampled for comparison. A 200-base-pair segment of hypervariable segment 2 (HVS2) of the mtDNA control region was sequenced in all individuals. In the Indian castes 25 distinct haplotypes are identified. Aside from the Cambridge reference sequence, only two haplotypes are shared between caste populations. Middle castes form a highly supported cluster in a neighbor-joining network. Mean nucleotide diversity within each caste is 0.015, 0.012, 0.011, and 0.012 for the Brahmin, Yadava, Kapu, and Relli, respectively. mtDNA variation is highly structured between castes (GST = 0.17; p < 0.002). The effects of social structure on mtDNA variation are much greater than those on variation measured by traditional markers. Explanations for this discordance include (1) the higher resolving power of mtDNA, (2) sex-dependent gene flow, (3) differences in male and female effective population sizes, and (4) elements of the kinship structure. Thirty distinct haplotypes are found in Africans, 17 in Asians, and 13 in Europeans. Mean nucleotide diversity is 0.019, 0.014, 0.009, and 0.007 for Africans, Indians, Asians, and Europeans, respectively. These populations are highly structured geographically (GST = 0.15; p < 0.001). The caste populations of Andhra Pradesh cluster more often with Africans than with Asians or Europeans. This is suggestive of admixture with African populations.

Base Sequence↗

PubMed1995

A gene for ulnar-mammary syndrome maps to 12q23-q24.1.

Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty and genital anomalies. We report the mapping of a gene causing UMS to chromosome 12q23-24.1. Linkage analysis generated a positive lod score of 6.21 at theta = 0.00 with the marker D12S79, and recombinants bracket the UMS gene to a 21 cM region. This region contains a locus for Holt-Oram syndrome (HOS) suggesting that the genes for UMS and HOS may be allelic or closely linked. The identification of the gene causing UMS will be an important step toward understanding the molecular mechanisms that control limb and apocrine gland development.

Abnormalities, Multiple↗

PubMed1995

Population genetics of trinucleotide repeat polymorphisms.

Trinucleotide repeats at five disease loci (DM, DRPLA, HD, SBMA and SCA1) were surveyed in phenotypically normal individuals from three continental populations. This is the first analysis to examine the population dynamics of these five disease-related trinucleotide repeats in the same individuals from worldwide populations. Roughly half of all alleles observed at each locus are shared between all continental groups. For three loci, disease prevalence in each population corresponds with the number of alleles in the upper tail of the allele-size distribution. The allele-size distributions of African, Asian and Caucasian groups show a high degree of variation, and gene diversity estimates for trinucleotide repeat loci exceed estimates derived from dinucleotide or tetranucleotide repeats. Analyses that compared infinite alleles and stepwise mutation models suggest that normal variation at trinucleotide loci is not generated by stepwise mutation alone. Trees constructed for subpopulations using trinucleotide repeat loci show accurate continental clustering. Interpopulation genetic distance estimates show remarkable similarity to distance estimates produced from tetranucleotide repeats or nuclear restriction site polymorphisms. This finding is especially noteworthy in light of the fact that trinucleotide repeat polymorphisms at these loci can cause disease, while restriction site and tetranucleotide polymorphisms appear to be selectively neutral. In contrast, genetic distance estimates from trinucleotide loci are poorly correlated with genetic distance estimates from mitochondrial sequence data.

Alleles↗