Chapter 2

Pedigree analysis
Controlled experimental crosses not possible in humans Analyze pedigrees and hope informative mating have been made by chance

Human and medical genetics

Symbols in pedigree analysis

Unaffected male Unaffected female Carriers Affected male Affected female Line indicates a mating

Medical genetics
o Study of rare inherited disorders
autosomal recessive autosomal dominant X-linked recessive X-linked dominant

Autosomal recessive disorders

Autosomal recessive disease genes

o Both parents must carry a recessive allele to have affected child
will affect 1/4 of children; 1/2 will be heterozygous carriers loss of function mutations

Examples
Albinism Cystic fibrosis Sickle-cell anemia -thalassemias (globin) Phenylketonuria

Sample pedigree for a recessively inherited trait

I

1
II

1
III

2 1

3 2

IV

consanguineous marriage

Two unaffected parents have an affected child Both males and females affected Skips generations Appears after consanguineous marriage

AA

Aa

AA Aa

Aa

Aa Aa

AA

aa

A_

A_

aa

A_

Important feature of pedigrees

Mendelian rules at work but Mendelian ratios not visible

Identifying carriers using molecular biology

RFLP Screening for Human Diseases -Sickle cell anemia

A change in the #6 amino acid of the globin chain of hemoglobin Glutamic acid to valine A to T

Hb A /

175 bp
probe
Normal -Globin allele HbA

201 bp

376 bp

Eliminates a site recognized by DdeI.

probe

Sickled -Globin allele HbS

Frequency of recessive alleles

Cystic fibrosis
most frequent genetic lethal disease of childhood (1/3700)

Autosomal Dominant Diseases

Will affect half of children of an affected parent Most are late onset or variable penetrance.

Allele frequency 0.016 (1/62) Hardy Weinberg equation

Gain of function genes

Autosomal dominant diseases

Rare disorder that is dominant? A paradox? Dominance not related to frequency in the population

Examples of autosomal dominant disorders

Huntingtons disease Achondroplastic dwarfism Polydactyly Brachydactyly Piebald spotting

Hb A /

Hb s /

Restriction enzyme DdeI (recognition sequence: 5'-GTNAG-3') Probe Fragment of -globin coding sequence

Hb A

Hb s

Hb s

Achondroplasia
1/10,000 people Affected individuals A/a A/A Results in spontaneous abortion of the fetus

What is the probability that two Achondroplastic dwarfs will have an affected child? A/a X A/a Aa?

A A a

AA Aa

Aa aa

Answer = 2/3

Variable expressivity

Huntingtons Chorea
Late acting dominant allele Onset 35-40 years Irreversible and lethal

Huntingtons Chorea

Sample pedigree for a dominantly inherited trait

I
1 2

Pedigree analysis of autosomal polymorphisms

II
1 2 3 4 5 6

III
1 2 3 4 5 6

Affected children always have an affected parent Occurs in every generation Approximately half offspring are affected