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The human forkhead box O1A (FOXO1A) gene on chromosome 13q14.1 is a key transcription factor in insulin signaling in liver and adipose tissue and plays a central role in the regulation of key pancreatic β-cell genes including IPF1. We hypothesized that sequence variants of FOXO1A contribute to the observed defects in hepatic and peripheral insulin action and altered β-cell compensation that characterize type 2 diabetes (T2DM). To test this hypothesis, we screened the three exons, 3′ untranslated region, and 5′ flanking region for sequence variants in Caucasian and African-American individuals with early onset (<45 years) T2DM. We identified only six variants; none altered the coding sequence, and except for one variant in the 3′ untranslated region, they were rare or absent in Caucasians. To increase coverage of the gene, we selected seven additional variants in the large first intron and 5′ flanking region, thus providing 13 variants that spanned 116.4 kb. Based on frequency and linkage disequilibrium patterns in a subset of individuals, we selected eight SNPs to type in a Caucasian population comprising 192 unrelated nondiabetic control individuals and 192 individuals with T2DM, and 10 SNPs to type in 182 controls and 352 diabetic individuals of African-American ancestry. No variant was associated with T2DM (African-Americans, p > 0.08; Caucasians, p > 0.09). Of the 8 Caucasian SNPs, six comprised a single haplotype block spanning over 100 kb and including most of the large first intron. In contrast, no block was observed among SNPs typed in African-Americans. No haplotype was associated with T2DM. FOXO1A variation is rare and is unlikely to contribute to T2DM in either Caucasian or African-American populations.

<p>This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. </p><p>Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. </p><p>Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. </p><p>Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions. </p>

Genetic mapping contributes to the understanding of functional mechanisms that underlie the constitution of living organisms and their physiology. For example, genetic mapping can be used in conceiving new treatments of congenital or infectious diseases and in selecting plants and animals that have a higher and better production. The most common approaches of genetic mapping exploit the allelic segregation in a pedigree during only a few number of generations and, consequently, they do not have a sufficient resolution to allow an effective gene isolation and cloning. An alternative to these approaches is to study allelic associations along the history of a population. This requires accurate models of population demography, genetic inheritance and allelic associations. This thesis contributes to the modelling of allelic associations (linkage disequilibrium, LD) and to the assessment of the effects of selection and inbreeding. In a simulation framework, we fitted the multimarker-multiallelic LD with an exponential function characterised by two parameters: the distance (R) at which LD is independent of the genetic distance and the LD reached at this distance (residual LD, rs). As an application of this approach, the LD was estimated in five populations of pigs. We observed a long range LD (>10cM) that was explained by the random drift. Moreover, significantly increased LD was found in regions harbouring selected QTL (quantitative trait loci), suggesting an effect of selection. Fitting LD with the exponential model proposed in simulations indicated that mapping methods using LD (LDM) can achieve a resolution of ~3cM in the populations of pigs we have studied and can be powerful with a marker spacing of 5-10cM. As illustrated with these data from pigs, the model that we used to fit LD offers opportunities to characterise allelic association in populations, estimate the required marker density for genome-wide LD studies and determine the expected resolution of LDM. It is also shown that the proposed model can help overcoming the assumptions of asymptotic linkage equilibrium and independence between markers that are commonly made in LDM but are not always fulfilled.

This thesis focuses on the identification of genetic factors underlying two inherited human phenotypes: hearing loss and monoamine oxidase activity. Non-syndromic hearing loss segregating in a Swedish family was tested for linkage to 13 previously reported candidate loci for hearing disabilities. Linkage was found to two loci: DFNA12 (llq22-q24) and DFNA2 (lp32). A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the hypothesis of digenic inheritance of hearing disability in the Swedish family. Mutation screening of α-tectorin, a gene residing within the DFNA12 region revealed a mutation of a conserved amino acid (Cys to Ser), that segregated with the disease. The identification of the mutation added support to the involvement of α-tectorin in hearing disabilities. In contrast, no mutations were identified in two candidate genes at the DFNA2 locus, that were reported to cause hearing loss in other families. It is possible that the DFNA2 locus contains a third, not yet identified, hearing loss gene. Monoamine oxidase A (MAOA) and B (MAOB) catalyze the degradation of certain neurotransmitters in the central nervous system and are associated with specific behavioral and neuropsychiatric human traits. Activity levels of both monoamine oxidases (MAO) are highly variable among humans and are determined by unknown genetic factors. This study investigated the relationship of different MAO alleles with MAO mRNA levels and enzyme activity in human brain. Several novel DNA polymorphisms were identified in a group of Swedish individuals. Haplotypes containing several closely located MAOA polymorphisms were assessed in Asian, African, and Caucasian populations. The haplotype distribution and diversity pattern found among the three populations supported the occurrence of a bottleneck during the dispersion of modem humans from Africa. Allelic association studies conducted on postmortem human brain samples, revealed the association between a SNP in the MAOB intron 13, and different levels of both MAO enzyme activities. This suggested that this SNP is in linkage disequilibrium with at least one novel functional DNA polymorphism that controls MAO enzyme activities in human brain. The identification of functional polymorphisms regulating the activity of these enzymes will help to elucidate the involvement of MAO in human behavior and neuropsychiatric conditions.