Genetics Part 1 Dr Mohammed Hussein M B

Genetics Part. 1 Dr. Mohammed Hussein M. B. Ch. B, MSC, Ph. D, DCH (UK), MRCPCH

Genetics • Part 1: Single-Gene Disorders • Part 2: Population Genetics • Part 3: Cytogenetics

Single-Gene Disorders

Basic Definitions

46 Chromosomes 22 pairs of autosomes (autosomal chromosomes) 1 pair of Sex chromosome

The two chromosomes in each diploid pair are said to be homologs, or homologous chromosomes. X and Y chromosomes, have some homologous regions but the majority of genes are different.

No. of chromosomes • Gametes (ova and sperms) are haploid, have one copy of each type of chromosome (1– 22, X or Y). • Somatic cells (cells other than gametes) are diploid, having two copies of each type of autosome (1– 22) and either XX or XY

• Gene. Physically a gene consists of a sequence of DNA that encodes a specific protein. • Locus. The physical location of a gene on a chromosome is termed a locus. • Alleles. Variation (mutation) in the DNA sequence of a gene produces a new allele at that locus. Many genes have multiple alleles. • Polymorphism. When a specific site on a chromosome has multiple alleles in the population, it is said to be polymorphic (many forms).

Allele for brown eye color Locus for eye color gene Homologus pair of chromosomes Allele for blue eye color

Homozygous vs. Heterozygous alleles • Homozygous if the individual has the same allele on both homologous chromosomes at that locus. • Heterozygous if the individual has different alleles on the two homologous chromosomes at that locus. • Hemizygous if the individual has one allele on one of the two homologs.

Genotype vs. Phenotype • The genotype is the specific DNA sequence at a locus • The phenotype is generally understood as the expression of the genotype in terms of observable characteristics

Mutations

The Recurrence Risk • The recurrence risk is the probability that the offspring of a couple will express a genetic disease.

Pedigrees (Family Tree) • A patient’s family history is diagrammed in a pedigree.

I 1 2 II 1 3 2 4 5 III 1 4 3 2 IV 1 2 3 5 6 Child 2 in Generation IV IV-2 4

Child 11 in Generation III-11

1. 2. 3. 4. Autosomal Dominant Inheritance Autosomal Recessive Inheritance Sex - linked Dominant Inheritance Sex - linked Recessive Inheritance

Autosomal Dominant Inheritance • This is the most common mode of Mendelian inheritance. • Caused by alterations in only one copy of a gene pair. • This mean the condition occurs in the heterozygous state despite the presence of an intact copy of the relevant gene. • AD genes are located on the autosomal chromosomes, so males and females are equally affected.

• Suppose that A is a dominant allele that cause a disease • • • And a is a recessive allele that is normal Homozygous AA , aa Heterozygous Aa AA and Aa has disease aa is normal

aa Aa Normal Diseased

Aa A Diseased (Hetrozygous) a a A a a a 50 % Disease 50 % Normal aa Normal Punnett Square

Aa A Diseased (Hetrozygous) a A A a 75 % Disease a A a a a 25 % Normal Aa Diseased (Hetrozygous)

AA A Diseased (Homozygous) A a A a aa Normal 100 % Disease

Achondroplasia (Dwarfism)

Autosomal Dominant Pedigree AA Aa aa aa AA Aa aa

Familial hypercholesterolemia Huntington disease Neurofibromatosis type I Marfan syndrome Achondroplasia Spherocytosis

Neurofibromatosis type I

• AR alleles are clinically expressed only in the homozygous state. • The offspring must inherit one copy of the disease causing allele from each parent.

• Suppose that a is the disease allele and it is recessive. • • • So the normal allele is the dominant (A) Homozygous AA , aa Heterozygous Aa AA no disease aa has the disease Aa has no disease (but he/she is a carrier for the abnormal gene), Heterozygous carrier

Aa A Heterozygous carrier a 50 % Heterozygous Carrier A A a 75 % No Disease a A a a a 25 % Disease Aa Heterozygous carrier

Aa A Heterozygous carrier a A A A A a AA Homozygous normal 50 % Normal 50 % Carrier

Aa Aa aa

Carrier Risk This person wants to know his carrier risk

I II IV IV-1 Carrier risk for the individual IV-1 is: a) 25% b) 33% c) 50% d) 67% e) 75% Hetrozygous carrier 2/3 = 66. 67% = 67% Homozygous 1/3 = 33. 33% = 33%

Sickle cell anemia Cystic fibrosis Phenylketonuria (PKU) Tay-Sachs disease

Phenylketonuria (PKU)