Genes in Pedigrees & Populations Monogenic versus multifactorial inheritance: Over 6000 Mendelian characters are known in humans (OMIM databse www.ncbi.nlm.nih.gov/Omim/ Multifactorial trait may involve a small number of loci (oligogenic) or many loci (polygenic) Dichotomous characters are known as susceptibility genes while quantitative or continuous characters are known as quantitative trait loci (QTLs).

2. Mendelian Pedigree patterns: Dominance and recessiveness are properties of traits not genes. Example sickle cell anemia. Dominance describes the phenotype of the heterozygotes. - Males are hemizygous for loci on X and most Y so the problems of dominance and recessiveness do not apply to X- and Y-linked characters.

Five basic Mendelian Pedigree Patterns: - Autosomal dominant - Autosomal recessive - X-limked recessive - X-linked dominant - Y-linked

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- X inactivation disturbs the distinction between dominant & recessive X-linked conditions (manisfesting heterozygotes observed in X-linked recessive conditions). - Genes in the Xp-Yp 2.6MB homologous pairing region segregate like autosomal genes and not like sex-limnked genes and thus are called pseudoautosomal genes.

The mode of inheritance of a human trait requires the compilation of pedigrees from several families (50 or so) displaying the same trait. This is because: - numbers per family are too small - in recessive traits, # of affected children are greater than 1 out of 4. This is due to “biases of ascertainment.” - genetic counselors should emphasize that modes of inheritance are hypothesis and not facts.

One-gene-one enzyme hypothesis does not apply in humans because most enzymes are complexes encoded by many gene loci. This occurs because of 3 types of heterogeneity: - Locus heterogeneity - Allelic heterogeneity - Clinical heterogeneity Locus heterogeneity demonstrates complementation in human syndromes that result from failure of a complex pathway (e.g. hearing loss)

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Mitochondrial inheritance is complexed by matrilineal inheritance and heteroplasmy.

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3. Complications of the basic Mendelian pedigree patterns: Common recessive conditions mimic a dominant pedigree pattern. Example blood group O (Fig 4.5A). Dominant traits fail to manifest which is known as nonpenetrance (Fig 4.5B, autosomal dominant trait fails to manifest in some of the offspring). Age-related penetrance in late onset diseases (e.g. Huntington disease) which might be due slow tissue death or accumulation of noxious substances (see Fig 4.7).

Variable expression (Fig 4 Variable expression (Fig 4.5C, autosomal dominant inheritance of Waardenburg syndrome shows variable expression). Anticipation (a special type of variable expression) is the tendency of some variable dominant conditions to become more severe in successive generations. Geneticists should avoid misinterpreting anticipation with variable expression. Anticipation is caused in cases that are due to unstable expandable trinucleotide repeats (e.g. Fragile-X) cause by misalignment of such repeats during crossing over.

Expression of imprinted genes depends on parental origin (Fig 4 Expression of imprinted genes depends on parental origin (Fig 4.5D, autosomal dominant trait manifests only when inherited from the father; Fig 4.5E, genetic imprinting showing inheritance of an autosomal dominant syndrome only from the mother). Male lethality may complicate X-linked pedigrees. In some X-linked dominant conditions, the absence of the normal allele is lethal before birth. Thus affected males are not born (Fig 4.5F).

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New mutations may complicate pedigree analysis New mutations may complicate pedigree analysis. When a normal couple with no relevant family history have a child with severe abnormalities, pedigree analysis becomes very difficult. The problem may be autosomal recessive, autosomal dominant with a new mutation, X-linked recessive, or nongenetic. See Fig 4.5H as an example. New mutation can lead to mosaicism, at the somatic, gonadal (germinal), or at both the somatic and germinal levels. Fig 8 shows a new mutation in X-linked recessive Duchenne muscular dystrophy.

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Molecular analysis can be used to clarify mosicism cause by new mutations. In males (not in females) direct testing of gametes is feasible to detect germinal new mutations. In females somatic tissues can be used for analysis. A negative result using somatic tissue does not rule out germline mosaicism, but a positive result, in conjugation with an affected child, proves it (Fig. 4.9)

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Chimeras are the result fusion of two zygotes to form a single embryo or the limited colonization of one twin by cells from non-identical co-twin (Fig. 4.10) Chimerism is proved by finding too many parental alleles at several gene loci when examining pooled tissue samples. Example, blood-grouping centers occasionally discover chimeras among normal donors. Some interesx patients turn out to be 46,XY/46,XX.

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4. Genetics of multifactorial characters: Polygenic characters are the result of the additive effect of a large number of individual alleles (in different loci) and this results in a Normal (Gaussian) distribution in the pouplation. See Fig. 4.11

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5. Factors affecting gene frequencies: For a single gene locus, two alleles A1 and A2occupy that locus and the allele (gene) frequencies are: A1 = p A2 = q A1 + A2 = 1.0 The genotype frequencies in that locus are: p2 + 2pq + q2 = 1.0

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