Prepared By: Dr. Awatif Ali Alam

The study of distribution of genes in populations and of how these gene frequencies are maintained or changed. Population Genetics

Historical Background Gregor John Mendel (1865): origin of modern human genetics. Francis Galton and Colleagues: Studied variations predisposing to diseases. Foundation of human medical genetics was laid down during the first decade of this century.

Rediscovery of Mendel’s work at turn of century. Karl Landsteiner’s discovery of ABO blood group system in Archibald Garrod discovery of “Inborn Errors in Metabolism” in Historical Background cont…

Impact of Genetic Disease Physicians paid little attention to genetics during the first three decades of the previous century. Was not considered an intrinsic part of medicine. Hereditary conditions were rare or so rarely recognized. Genetics was developed by Zoologists and Botanists.

Probability Similarity between gene transmission and toss of a coin. A child receives his genotype from two parents. The chance that a child, both of whose parents are (Aa) will receive the (A) allele from each is ½ x ½ = ¼ Applies to sex ratios in families. Probability has no memory. Binomial distribution approximately equal probability of combination of two independent events.

For two-child families, the frequencies of different possible combinations of P & q presented by the binomial distribution of P & q:- (P & q) 2 = P pq + q 2 Families of 2 boys = p 2 = ½ + ½ = ¼ Families of 2 girls = q 2 = ½ x ½ = ¼ Families of a boy and a girl = 2pq = 2 x ½ x ½ = ½ Note:Primary and Secondary sex ratios.

Hardy Weinberg Principle: Expounded in Frequency of a hereditary disorder is independent of whether the disease is a dominant or recessive one. The Cornerstone of population genetics. Statement: [(Neglecting mutation, selection, gene flow, and genetic drift)] the gene frequency and genotype frequencies remain constant from generation to generation. P + q = 1

Importance of “H-W” Formula: Determining gene frequencies when the genotype incidence is known. Calculating the proportion of heterozygotes when the frequency of the recessive phenotype is known.

Importance of “H-W” Formula: cont… Example:- If the incidence of (PKU) is 1 in 10,000 live births, and it is a recessive condition then: q 2 = 1/10,000 = q = = 0.01 Where q is the gene frequency for PKU. The frequency of heterozygotes is 2 pq as: P + q = 1 P = 1 – 0.01 = pq = 2 (0.99 x 0.01) = about 1/50

Pedigree Patterns: The chief method of genetic study in man. DOMINANT CONDITION I. II } } AFFECTEDAFFECTED 123

Criteria for recognizing autosomal dominant inheritance: (Cont…) 1.Patients are heterozygotes. 2.Patients have one affected parent. 3.Boys and girls are equally likely to be affected.

Recessive Condition RECESSIVE CONDITION I. II APPARENTLY NORMAL AFFECTED

The criteria for recognizing autosomal recessive inheritance are:- 1.Patients are homozygotes. 2.Patients are the children of apparently normal parents who, are obligate heterozygotes. 3.One quarter of the sibs of the proband are affected. 4.Boys are affected as often as girls. 5.Affected people who marry normal people will have apparently normal children.

X-Linked Inheritance I. II HOMOZYGOTE NORMAL III. HEMIZYGOTE AFFECTED HETEROZYGOTE CARRIER HEMIZYGOTE AFFECTED

Criteria for recognizing X-linked inheritance are: 1.Affected boys are hemizygous. 2.50% of daughters are carriers. 3.50% of sons are affected. 4.Affected fathers do not have affected sons. 5.All daughters of affected fathers are carriers.

Consanguinity: There is an above – average risk of producing homozygous off springs for a certain recessive gene. Risk increases with closeness of relationship of the parents. If prevalent in a population can disturb “H-W” equilibrium by increasing the proportion of homozygotes at the expense of heterozygotes “Genetic Isolates”.

Coefficient of in Breeding: Is the probability that an individual being homozygous for a certain locus by receiving both alleles of this locus from ancestral source. Offspring of first-cousin marriage is homozygous at 1/16 of his loci.

Factors Affecting Gene Frequency in a Population: 1.Non-random mating. 2.Altered mutation rate. 3.Selection. 4.Small populations. 5.Migration.

1.Non-Random Mating: The offspring of these mating are at an increased risk of homozygosity for any recessive alleles carried by the common ancestor(s).

2.Altered Mutation Rate: New hereditary variations arise by mutation, and the new gene is called a mutant. The spontaneous mutation rate (u) varies for different loci: (u = n/2 N) (n = no. of cases with mutent gene / N = Total No. of births) Who have normal parents The rate is easier to measure in dominant genes. Dominant traits require a mutation rate in only one of the two gametes concerned.

3.Selection: Genetic selection acts on the individual phenotypes and either favours or hinders reproduction and thus the propagation of that individual’s genotype. Acts by modifying an individual’s biological fitness (F). For an autosomal dominant trait, any increase in (F), will rapidly alter the gene frequency over the next few generations to a new equilibrium.

Selection: (Cont’d) Selection against a recessive genotype is less effective and result in a slow change in gene frequencies. For X-Linked recessive trait, the situation is intermediate between autosomal dominant and recessive.

4.Small Populations: For religious, geographical, tribal or other reasons a small group of individuals may become genetically isolated from the rest of the population (genetic isolates). By chance one allele may fail to be passed on to the next generation and so disappear (extinction) leaving only the alternative allele at that locus (fixation).

5.Migration: Migrant individuals will modify the gene pool of their descendents. ABO blood group system – B allele.

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