Complex Traits - Cell Biology - Lecture Slides, Slides of Cell Biology

Download Complex Traits - Cell Biology - Lecture Slides and more Slides Cell Biology in PDF only on Docsity!

Genetic Heterogeneity and

Complex Traits

• Allelic heterogeneity
• Nonallelic heterogeneity
• r
• Twin studies
• Sib-pair analysis

Each of the heritable human traits that we have discussed in recent weeks is monogenic

Each of these traits was quite straightforward from a Mendelian perspective:

invariably caused by mutation in the same gene.

Sickle cell disease: autosomal recessive

Phenylketonuria: autosomal recessive

Huntington's disease: autosomal dominant

genetic homogeneity

all affected individuals have the same mutation in the same gene

DUCHEYNNE BECKER

TWO MUSCULAR DYSTROPHIES

retinitis pigmentosa (RP):

• degeneration of retina (accompanied by deposits of pigment in retina)  progressive visual impairment  blindness
• population prevalence of 1/3,
• one of most common causes of blindness among middle aged in developed countries
• autosomal recessive inheritance in 84% of affected families
• autosomal dominant inheritance in 10% of affected families
• X-linked recessive inheritance in 6% of affected families
• At least 66 different genetic loci implicated

but RP appears to be result of a single gene mutation in any given family, at least in most cases

NON-ALLELIC HETEROGENEITY

This "candidate gene" approach will become increasingly prominent given:

• Complete sequence of human genome
• Falling cost of sequencing

Complete sequence of human genome (rough draft published in 2001; reference grade sequence expected in 2003)

Perhaps 10 years from now, scientists will routinely sequence the entire genomes of individuals with unexplained phenotypes.

r = coefficient of relationship between two individuals

= likelihood of sharing by descent a given allele at a given locus = expected proportion of all alleles (at all genes) that two individuals share by descent

coefficient of relationship, r ≠ inbreeding coefficient, F

(likelihood that an individual is homozygous by descent at a given locus)

First cousins

Aunt/niece

Siblings

Parent-child

Relationship degree r

1st 1/ 1st 1/ 2nd 1/ 3rd 1/

Phenotypic concordance in monozygotic (MZ; identical) and dizygotic (DZ; fraternal) twins

MZ twins arise when a developing embryo (derived from one zygote; fertilization of one egg by one sperm) splits into two parts, each giving rise to a baby

DZ twins arise from two separate, but nearly simultaneous fertilization events.

Parent-child 1st 1/ Siblings 1st 1/ Aunt/niece 2nd 1/ First Cousins 3rd 1/

DZ twins

MZ twins

Relationship degree r

1st 1/

MZ twins DZ twins Interpretation

Concordance Rates in

environmental (contagious) environment + multiple genes

Twin studies:

Concordance = both twins display phenotype in question

Discordance = one twin displays phenotype in question, other does not

Schizophrenia

Coronary heart disease

Insulin-dependent diabetes

Cleft lip

Measles

Cystic fibrosis

Sickle cell disease

Huntington's disease (^) 100% 50% autosomal dominant

100% 25% autosomal recessive 100% 25% autosomal recessive 97% 94% 40% 4%

30% 6% environment, ≥1 gene

46% 12% environment, ≥1 gene 46% 14% environment, ≥1 gene

Hamer and colleagues then employed concordant sib-pair analysis , variation on conventional genetic linkage analysis that

1. requires no knowledge of mode of inheritance
2. unaffected by incomplete penetrance
3. can tolerate some degree of non-allelic heterogeneity

Sib-pair analysis =

search for nonrandom sharing of alleles between phenotypically concordant sibs

Hamer and colleagues (Science 261:321-327 [1993]) identified 40 nuclear families in which there were two homosexual brothers.

C/Y A/B

Identical by descent (IBD)

A/Y A/Y

B/Y B/Y

A/Y B/Y Nonidentical B/Y A/Y

In each of the 40 families, they studied the transmission of X-linked SSRs from the mother to the homosexual sons. For an X-linked SSR, there are two possible genotypes in each son, and thus there are four possible combinations of genotypes in the two sons:

Suggests that a gene on distal long arm of X chromosome contributes to the development of male homosexuality -- in some but not all cases.

p = probability, given the null hypothesis, of observing the data (or data even more diverged from the null expectations)

p <<< 0.

The table of critical values of the X distribution has been removed due to copyright considerations.ew Text

2