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Biomedical subjects

G W Montgomery

Publications and source records attributed to G W Montgomery.

At least 19 recordsLinked to original sources
PubMed2006

Genomewide scans of red cell indices suggest linkage on chromosome 6q23.

BACKGROUND: The red cell indices quantify the size, number and oxygen-carrying ability of erythrocytes. Although the genetic basis of many monogenic forms of anaemia is well understood, comparatively little is known about the genes responsible for variation in the red cell indices among healthy participants. OBJECTIVE: To identify quantitative trait loci (QTLs) responsible for normal variation in the red cell indices of 391 pairs of dizygotic twins who were measured longitudinally at 12, 14 and 16 years of age. RESULTS: Evidence suggesting linkage of red cell indices to haemoglobin concentration (LOD = 3.03) and haematocrit (LOD = 2.95) on chromosome 6q23, a region previously identified as possibly harbouring a QTL for haematocrit, was found. Evidence for linkage to several other regions of the genome, including chromosome 4q32 for red cell count and 7q for mean cell volume, was also found. In contrast, there was little evidence of linkage to the chromosomal regions containing the genes for erythropoietin (7q21) and its receptor (19p13.2), nor to the regions containing the genes for the haemoglobin alpha (16p13.3) and beta chains (11p15.5). CONCLUSION: Findings provide additional evidence for a QTL affecting haemoglobin and haematocrit on chromosome 6q23. In contrast, polymorphisms in the genes coding for erythropoietin, its receptor and the haemoglobin alpha and beta chains do not appear to contribute substantially to variation in the red cell indices between healthy persons.

Adolescent↗
PubMed2006

Effect of the BDNF V166M polymorphism on working memory in healthy adolescents.

Brain-derived neurotrophic factor (BDNF) may play a role in modulating memory function and there is growing evidence that the BDNF V166M polymorphism may influence episodic memory in humans. However, previous association studies examining this polymorphism and working memory are inconsistent. The current study examined this association in a large sample of adolescent twin-pairs and siblings (785 individuals from 439 families). A range of measures (event-related potential, general performance and reaction time) was obtained from a delayed-response working-memory task and total association was examined using the quantitative transmission disequilibrium tests (QTDT) program. Analyses had approximately 93-97% power (alpha= 0.05) to detect an association accounting for as little as 2% of the variance in the phenotypes examined. Results indicated that the BDNF V166M polymorphism is not associated with variation in working memory in healthy adolescents.

Adolescent↗
PubMed2005

Genome-wide scan of IQ finds significant linkage to a quantitative trait locus on 2q.

A genome-wide linkage scan of 795 microsatellite markers (761 autosomal, 34 X chromosome) was performed on Multidimensional Aptitude Battery subtests and verbal, performance and full scale scores, the WAIS-R Digit Symbol subtest, and two word-recognition tests (Schonell Graded Word Reading Test, Cambridge Contextual Reading Test) highly predictive of IQ. The sample included 361 families comprising 2-5 siblings who ranged in age from 15.7 to 22.2 years; genotype, but not phenotype, data were available for 81% of parents. A variance components analysis which controlled for age and sex effects showed significant linkage for the Cambridge reading test and performance IQ to the same region on chromosome 2, with respective LOD scores of 4.15 and 3.68. Suggestive linkage (LOD score>2.2) for various measures was further supported on chromosomes 6, 7, 11, 14, 21 and 22. Where location of linkage peaks converged for IQ subtests within the same scale, the overall scale score provided increased evidence for linkage to that region over any individual subtest. Association studies of candidate genes, particularly those involved in neural transmission and development, will be directed to genes located under the linkage peaks identified in this study.

Chromosome Mapping↗
PubMed2005

Linkage analyses of event-related potential slow wave phenotypes recorded in a working memory task.

Working memory is an essential component of wide-ranging cognitive functions. It is a complex genetic trait probably influenced by numerous genes that individually have only a small influence. These genes may have an amplified influence on phenotypes closer to the gene action. In this study, event-related potential (ERP) phenotypes recorded during a working-memory task were collected from 656 adolescents from 299 families for whom genotypes were available. Univariate linkage analyses using the MERLIN variance-components method were conducted on slow wave phenotypes recorded at multiple sites while participants were required to remember the location of a target. Suggestive linkage (LOD > 2.2) was found on chromosomes 4, 5, 6, 10, 17, and 20. After correcting for multiple testing, suggestive linkage remained on chromosome 10. Empirical thresholds were computed for the most promising phenotypes. Those on chromosome 10 remained suggestive. A number of genes reported to regulate neural differentiation and function (i.e. NRP1, ANK3, and CHAT) were found under these linkage peaks and may influence the levels of neural activity occurring in individuals participating in a spatial working-memory task.

Adolescent↗
PubMed2004

A major quantitative trait locus for CD4-CD8 ratio is located on chromosome 11.

CD4-CD8 ratio is an important diagnostic measure of immune system functioning. In particular, CD4-CD8 ratio predicts the time taken for progression of HIV infection to acquired immune deficiency syndrome (AIDS) and the long-term survival of AIDS patients. To map genes that regulate differences between healthy individuals in CD4-CD8 ratio, we typed 757 highly polymorphic microsatellite markers at an average spacing of approximately 5 cM across the genome in 405 pairs of dizygotic twins at ages 12, 14 and 16. We used multipoint variance components linkage analysis to test for linkage between marker loci and CD4-CD8 ratio at each age. We found suggestive evidence of linkage on chromosome 11p in 12-year-old twins (LOD=2.55, P=0.00031) and even stronger evidence of linkage in the same region at age 14 (LOD=3.51, P=0.00003). Possible candidate genes include CD5 and CD6, which encode cell membrane proteins involved in the positive selection of thymocytes. We also found suggestive evidence of linkage at other areas of the genome including regions on chromosomes 1, 3, 4, 5, 6, 12, 13, 15, 17 and 22.

Adolescent↗
PubMed2001

Human twinning is not linked to the region of chromosome 4 syntenic with the sheep twinning gene FecB.

The tendency to dizygotic (DZ) twinning is inherited in both humans and sheep, and a fecundity gene in sheep (FecB) maps to sheep chromosome 6, syntenic with human 4q21-25. Our aim was to see whether a gene predisposing to human DZ twinning mapped to this region. DNA was collected from 169 pairs and 17 sets of 3 sisters (trios) from Australia and New Zealand who had each had spontaneous DZ twins, mostly before the age of 35, and from a replication sample of 111 families (92 affected sister pairs) from The Netherlands. Exclusion mapping was carried out after typing 26 markers on chromosome 4, of which 8 spanned the region likely to contain the human homologue of the sheep FecB gene. We used nonparametric affected sib pair methods for linkage analysis [ASPEX 2.2, Hinds and Risch, 1999]. Complete exclusion of linkage (lod < -2) of a gene conferring a relative risk for sibs as low as 1.5 (lambda(s) > 1.5) was obtained for all but the p terminus region on chromosome 4. Exclusion in the syntenic region was stronger, down to lambda(s) = 1.3. We concluded that if there is a gene influencing DZ twinning on chromosome 4, its effect must be minor.

Adult↗
PubMed2001

Mutations in the follicle-stimulating hormone receptor and familial dizygotic twinning.

Concentrations of follicle-stimulating hormone (FSH) have an important role in multiple ovulation. An association has been reported between mutations in the FSH receptor (FSHR) in a family with increased twinning frequency. We sequenced the transmembrane region of FSHR (located on chromosome 2) in 21 unrelated mothers of dizygotic twins and found no differences to the published sequence. A linkage study of 183 sister pairs and trios, in which all sisters had given birth to spontaneous dizygotic twins, excluded linkage to this region of chromosome 2. We conclude that mutations in FSHR are not a common cause of familial dizygotic twinning.

Chromosomes, Human, Pair 2↗
PubMed2001

The genetics of cognitive processes: candidate genes in humans and animals.

It has been hypothesized that numerous genes contribute to individual variation in human cognition. An extensive search of the scientific literature was undertaken to identify candidate genes which might contribute to this complex trait. A list of over 150 candidate genes that may influence some aspect of cognition was compiled. Some genes are particularly strong candidates based on evidence for involvement in cognitive processes in humans, mice, and Drosophila melanogaster. This survey confirms that many genes are associated with cognitive variation and highlights the potential importance of animal models in the study of human cognition.

Animals↗
PubMed2001

Highly prolific Booroola sheep have a mutation in the intracellular kinase domain of bone morphogenetic protein IB receptor (ALK-6) that is expressed in both oocytes and granulosa cells.

The Booroola fecundity gene (FecB) increases ovulation rate and litter size in sheep and is inherited as a single autosomal locus. The effect of FecB is additive for ovulation rate (increasing by about 1.6 corpora lutea per cycle for each copy) and has been mapped to sheep chromosome 6q23-31, which is syntenic to human chromosome 4q21-25. Bone morphogenetic protein IB (BMP-IB) receptor (also known as ALK-6), which binds members of the transforming growth factor-beta (TGF-beta) superfamily, is located in the region containing the FecB locus. Booroola sheep have a mutation (Q249R) in the highly conserved intracellular kinase signaling domain of the BMP-IB receptor. The mutation segregated with the FecB phenotype in the Booroola backcross and half-sib flocks of sheep with no recombinants. The mutation was not found in individuals from a number of sheep breeds not derived from the Booroola strain. BMPR-IB was expressed in the ovary and in situ hybridization revealed its specific location to the oocyte and the granulosa cell. Expression of mRNA encoding the BMP type II receptor was widespread throughout the ovary. The mutation in BMPR-IB found in Booroola sheep is the second reported defect in a gene from the TGF-beta pathway affecting fertility in sheep following the recent discovery of mutations in the growth factor, GDF9b/BMP15.

Activin Receptors↗
PubMed2001

Genes controlling ovulation rate in sheep.

Sheep provide a valuable model for studying the genetic control of ovulation rate. Recent progress includes the identification of mutations in BMP15 (bone morphogenetic protein 15) that increase ovulation rate in heterozygous carriers and block follicular development in homozygous carriers. The genes characterized to date appear to act principally within the ovary and result in earlier maturity of granulosa cells and reduced follicular size. There may also be other sites of action, and increased FSH concentrations appear to be important in the expression of the FecB phenotype. A new locus on the X chromosome in New Zealand Coopworth sheep increases ovulation rate by about 0.4 and is maternally imprinted. Results from studies in the Cambridge and Belclare breeds indicate that further genes remain to be characterized. Finding the first mutations leading directly to variation in ovulation rate is likely to speed up the identification and molecular analysis of these other genes. There is still much to learn about follicular development and the control of litter size from genetic models in sheep.

Animals↗
PubMed2000

Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner.

Multiple ovulations are uncommon in humans, cattle and many breeds of sheep. Pituitary gonadotrophins and as yet unidentified ovarian factors precisely regulate follicular development so that, normally, only one follicle is selected to ovulate. The Inverdale (FecXI) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecXI/FecX+; ref. 1), but primary ovarian failure in homozygotes (FecXI/FecXI; ref. 2). Germ-cell development, formation of the follicle and the earliest stages of follicular growth are normal in FecXI/FecXI sheep, but follicular development beyond the primary stage is impaired. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females. We report here that the FecXI locus maps to an orthologous chromosomal region syntenic to human Xp11.2-11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Whereas BMP15 is a member of the transforming growth factor beta (TGFbeta) superfamily and is specifically expressed in oocytes, its function is unknown. We show that independent germline point mutations exist in FecXI and FecXH carriers. These findings establish that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.

Amino Acid Sequence↗
PubMed2000

Dizygotic twinning is not linked to variation at the alpha-inhibin locus on human chromosome 2.

Natural multiple pregnancy in women leading to dizygotic (DZ) twins is familial and varies across racial groups, suggesting a genetic predisposition. Mothers of DZ twins have a higher incidence of spontaneous multiple ovulation and elevated FSH concentrations. FSH release is controlled by feedback of inhibin peptides from the ovary, and immunization against inhibin alpha-subunit results in an increased ovulation rate in animals. The inhibin alpha-subunit is therefore a candidate gene for mutations that may increase the frequency of DZ twinning. Restriction digests of a PCR product from exon 1 with the enzyme SpeI detects a C/T polymorphism at bp 128 with two alleles of 447 and 323/124 bp. The polymorphism was typed in 1,125 individuals from 326 pedigrees with 717 mothers of spontaneous DZ twins. The alpha-inhibin locus mapped within 3 centimorgans of D2S164, and linkage with DZ twinning was excluded [decimal log odds ratio (LOD) score, -2.81 at theta = 0]. There was complete exclusion of linkage (LOD, less than -2) of a gene conferring relative risk 1.8 (lambdas, >1.8) across the chromosome, except at the p-terminus region and a small peak (maximum LOD score, 0.6) in the region of D2S151-D2S326. Analysis using either recessive or dominant models excluded linkage with DZ twinning in this population (LOD score, less than -2.5) across chromosome 2. We conclude that dizygotic twinning is not linked to variation in the alpha-inhibin locus. The results also suggest that mutations in other candidates on chromosome 2, including the receptor for FSH and the betaB-inhibin subunit (INHBB) cannot be major contributors to risk for DZ twinning.

Chromosome Mapping↗
PubMed2000

Genome mapping in ruminants and map locations for genes influencing reproduction.

Genetic maps provide a critical link between genes and phenotypes and are essential tools in the search for the genetic basis of variation in reproductive traits. Genes coding for hormones, growth factors, receptors, binding proteins, transcription factors and enzymes that influence the development and function of the reproductive axis have been assigned to genetic maps of ruminants and locations can be found in the respective genome databases. In addition, comparative information on gene structure and map location will help define the functions of essential genes. Gene locations from other species can be used because of extensive comparative links among mammalian gene maps. Large-scale projects to sequence genes and the ability to map these genes in parallel in radiation hybrid panels of different species will greatly improve the maps and our ability to translate between them. Cloning the genes responsible for genetic differences in fertility and fecundity in ruminants is likely to provide valuable clues to understanding ovarian function and germ cell development.

Animals↗
PubMed1999

Genomic imprinting of the insulin-like growth factor 2 gene in sheep.

A number of genes in the human and mouse genomes are subject to genomic imprinting, with selective inactivation of one allele of a gene in a parent-of-origin specific manner. One of the first imprinted genes identified was the Insulin-like Growth Factor 2 gene (IGF2), which promotes growth of the fetus and is expressed from only the paternal allele in most tissues in both the mouse and human. The aim of this study was to establish the imprinting status of IGF2 in sheep (Ovis aries). Sheep provide an interesting model to study imprinting, owing to differences in their placental development and the fact that they have been subject to strong artificial selection for various production traits. We report the identification of a length polymorphism in the transcribed 3'-untranslated region of the ovine IGF2 gene. This polymorphism was used to map IGF2 to sheep Chromosome (Chr) 21 and demonstrate that IGF2 is indeed imprinted in sheep, being expressed from the paternal allele. We also report that the developmental switch from imprinted IGF2 expression in the fetal liver to biallelic IGF2 expression in the adult liver, which occurs in the human but not mouse, also occurs in sheep. Differences in male- and female-specific recombination values reported around the IGF2 locus in the human were also observed around the ovine IGF2 locus. The techniques developed in this study will enable the imprinting status of IGF2 to be assessed in a variety of tissues and stages of development in normal sheep.

3' Untranslated Regions↗
PubMed1999

Determination of genetic relationships among five indigenous Chinese goat breeds with six microsatellite markers.

Microsatellite variation was analyzed in five Chinese indigenous goat breeds, which include four Cashmere breeds (Tibetan, Neimonggol, Liaoning, Taihang) and one Hubei local breed (Matou) used for meat production. Five ovine and one bovine microsatellites, selected from eight ovine microsatellites and five bovine microsatellites were suitable for use in this study. With these six microsatellites, allele frequencies, heterozygosity, polymorphism information content (PIC) and effective allele number were calculated. A neighbor-joining tree was constructed using Nei's standard genetic distance (1978). In the tree, Neimonggol and Liaoning were grouped together, then with Taihang; while Tibetan and Matou individually had their own branch. The genetic relationship of five breeds corresponds to their history and geographic origins.

Animals↗