II. Multifactorial traits.

III. Familial traits of uncertain origin.

Terms

Errata Page 381, Table 16.1: Most geneticists do not distinguish between polygenic and multigenic. Page 382, last sentence of first paragraph: Definition of epistasisshould be "variation at a locus that obscures phenotypic expression of variation at a second locus." Page 392, paragraph 2: Females have about twice the risk of developing bipolar illness as males. Page 399, Figure 16.15 and paragraphs 3-4: The pedigree and discussion speak of maternal inheritance and maternal transmission. However, the correct reference is to X-linked recessive transmission. Maternal inheritance describes traits transmitted by mitochondria.

I. Behavioral traits that show monofactorial inheritance are treated like any other inherited traits.

A. There are numerous behavioral variations in animals that are associated with specific genotypes. One of the more interesting is a recently discovered behavioral pattern in mice that results from homozygosity for nonfunctional fos (an oncogene). In contrast to normal mice, fos¯/fos¯ mothers ignore their offspring, allowing them to die from lack of care and nourishment.

B. Huntington disease is a degenerative disease of the central nervous system with onset typically in the 30-50 year age range. Transmission has long been recognized as autosomal dominant.

C. Lesch-Nyhan syndrome is an X-linked recessive disorder caused by lack of the enzyme hypoxanthine phosphoribosyl transferase (HPRT). The phenotype includes mental retardation. There is a strong compulsion for self-mutilation not found in other MR patients with similar IQ.

D. Hyperekplexia ("startle disease") is a rare disorder characterized by muscle rigidity in infants and exaggerated startle response. As individuals age, the muscle rigidity abates, but the startle response remains. Unexpected noise or touch may induce sudden muscle contractions, with unchecked falling and numerous resultant injuries.

1. The disorder is most commonly inherited as an autosomal dominant trait. However, in one family, children of a consanguineous marriage were affected, indicating the possibility of recessive inheritance also.

2. Both the dominant and recessive forms have been shown to result from mutations in the glycine receptor locus GLRA1. Glycine functions as a neurotransmitter in the central nervous system. The glycine receptors are cell surface receptors that bind glycine, modifying CNS function. The GLRA1 locus is on chromosome 5 near the end of the long arm.

3. There are other "startle" diseases, but most have not been studied genetically very successfully.

E. Alzheimer disease (AD) involves loss of mental function, particularly memory, with age. In most cases, the onset is after age 60, and the causes are largely unknown. In about 10% of cases, onset is before age 60 (early onset cases) and the disorder is inherited as an autosomal dominant trait.
1. In the brain, there are deposits within cells and also extracellular plaques, the latter formed from a polypeptide called beta-amyloid. Beta-amyloid is a fragment of a protein, amyloid precursor protein (APP) coded by a gene on chromosome 21.

2. Several autosomal loci that cause early-onset AD have been identified, with mutations at any one of the loci being sufficient to cause AD. These loci have been mapped to chromosomes 1, 14, and 21. The rare cases that map to 21 involve mutations in the APP locus. The loci on chromosomes 1 and 14 are called presenilin 2 and presenilin 1

. 3. AD is an example of genetic heterogeneity, with any of several genotypes causing the same phenotype.

4. Person's with Down syndrome develop AD at 40-50 years of age. The cause has not been proved but is thought to be the presence of three copies of the APP gene that occurs in trisomy 21.

F. Brunner syndrome refers to an unusual family reported from Holland in which certain males over several generations showed abnormal aggressive and impulsive behavior. This included arson, rape, and exhibitionism. Women in the family perceived a distinct difference between the normal and affected males. In five of the males who were studied, there was a mutation in the monoamine oxidase A gene (MAOA) that changed a glutamine codon to a termination codon. MAOA is on the X chromosome, consistent with the transmission pattern in this family.

G. Other single gene conditions that have major behavioral consequences are Charcot-Marie-Tooth syndrome, Friedreich ataxia, and Menkes kinky-hair syndrome, all described in the textbook.

A. Intelligence, as measured by IQ, has shown high heritability in most studies.
1. IQ is constructed to measure one’s performance as compared to the variation of persons of the same age in the population of which one is a member.

2. Heritability is high but refers only to the population that is studied. Different populations in different environments can show differences in heritability, both because the allele frequencies are different among them and because the extent of the environmental variations varies. Whatever the heritability in a particular population, one cannot extrapolate to other populations, nor can one draw conclusions about the possible contributions of heredity and environment to the differences in IQ among populations.

3. Very low intelligence (mental retardation) is often transmitted as a monofactorial trait, often as part of a complex syndrome. High intelligence seems to depend on favorable alleles at many loci, i.e. it is multifactorial.

B. In contrast to early-onset Alzheimer disease, late-onset Alzheimer disease clusters in families but not in a pattern that is consistent with simple inheritance.
1. One risk factor is the APOE (apolipoprotein E) locus on chromosome 19. There are three common alleles: E2, E3, and E4. Persons homozygous for E4 are virtually certain to develop AD by age 80. Persons heterozygous for E4 have a substantially increased risk of AD compared to persons who lack E4 but at somewhat later ages.

2. The function of APOE is in transport of cholesterol and triglycerides in the blood. It is uncertain how the different APOE alleles cause such a dramatic difference in risk of AD. The E4 allele is also associated with high LDL cholesterol and coronary disease.

3. The occurrence of aluminum in AD plaques raised the question of whether excessive exposure to aluminum might be the cause of AD. This has been ruled out.

A. Schizophrenia is a form of psychosis that involves disturbed thought, hallucinations, and other features. It occurs in ca. 1% of population, with strong familial clustering.
1. Pedigree analysis shows schizophrenia to be neither a simple dominant nor recessive trait.

2. In some populations, there are pedigrees that resemble autosomal inheritance, although there are individuals in the pedigrees who are inconsistent with Mendelian expectations.

3. With the recent availability of closely spaced genetic markers, it is possible to test for cosegregation of risk of schizophrenia and markers that are distributed throughout the genome. Recent studies in a number of populations suggest that in many families, a variant alleles at a loci on chromosomes 6, 8, and 13 contribute strongly to risk of schizophrenia. There is suggestive evidence of several other loci that also contribute to risk of schizophrenia.

B. Bipolar affective disorder (manic-depressive psychosis) shows very strong familial clustering.
1. Females are about twice as likely to be affected as males, which could be explained genetically only if it were an X-linked dominant trait. However, transmission pattern in families usually is not consistent with X-linked dominant inheritance.

2. A number of studies of BPAD are underway. Although several locations of BPAD genes have been reported, none has been established with certainty. Several studies have provided support for loci on 18p and 18q. Because of the existence of some excellent pedigrees, it should only be a matter of time until one or more BPAD loci are mapped.

C. Tourette syndrome is a common syndrome that strongly clusters in families. However, the genetic basis has not been established. This is thought to be in part due to the great variation in expression and the difficulty in diagnosing individuals has having Tourette syndrome.

D. Alcoholism clusters strongly in families and is thought by many to have a genetic basis. Efforts to identify a gene for alcoholism have not been successful.

E. There have been suggestions and some evidence (weak) that male homosexuals have biological differences from heterosexual males. These observations have been used to argue that sexual orientation has a genetic component.

1. The frequency of male MZ twins concordant for homosexuality is greater than the frequency in DZ twins. However, this type of evidence is of doubtful value for a behavioral trait.

2. Recently, two studies have tested the hypothesis that there is a locus on the X chromosome that predisposes to male homosexuality. The studies tested for cosegregation of X-chromosome markers and homosexuality in brothers and in maternal uncle-nephew pairs. The homosexual pairs appeared to share haplotypes near the end of the X chromosome more often than would be expected by chance, suggesting that there may be a "gay" gene in this region. Lesbian pairs did not show this cosegregation. Other studies have failed to support these findings. Whatever the biological contributions to development of sexual orientation, there is at present no sound evidence that genetic variation makes a contribution.

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