Sex linkage and Pedigrees

1. Sex linkage and Pedigrees

2. Sex determination in mammals • In humans and some other organisms, X and Y chromosomes determine the sex of an individual. • This is because they carry certain genes that are critical in sex determination, such as the SRY gene on the mammalian Y chromosome, which controls testis formation. • Individuals with two similar sex chromosomes are the homogametic sex. (i.e. women XX) • Individuals with different sex chromosomes are the heterogametic sex. (i.e. men XY) • During the growth and development of females’ cells, one X chromosome is inactivated in each body cell. The inactivated X chromosome is visible in a female’s cells as a Barr body.

3. Sex determination in other organisms WZ Chromosome System • Males are homogametic (ZZ) and females are heterogametic (ZW). • Birds and strawberries are examples of the W/Z determination. XO Chromosome System • Only one sex chromosome. • Females are XX but males are XO, where the O refers to the absence of a matching sex chromosome. • In the XO chromosome system diploid number is therefore even in females and odd in males. Sex Determination by haplodiploidy • Males develop from unfertilised eggs and are therefore haploid. • Females develop from fertilised eggs and are diploid. Examples include wasps and bees. Sex Determination by environmental factors • Environmental sex determination may depend on: • temperature (e.g. turtles, crocodiles) • day length (shrimp) • richness and availability of food resources (e.g. nematodes).

4. X linked inheritance • Males receive their X chromosome from their mother – so they inherit all X-linked traits from their mothers. The alleles on this chromosome will determine the phenotype of X-linked traits regardless of whether the trait is dominant or recessive in heterozygous females. • All females inherit an X chromosome from each parent. The random nature of X chromosome inactivation means that heterozygous females express different alleles in different cells.

5. X linked inheritance • X-linked Recessive disorders • Show a pattern of transmission of the mutant phenotype from the female parent to male offspring. • Only females may be carriers of an X-linked recessive trait. • Examples of X-linked recessive disorders include haemophilia A, haemophilia C and red-green colour blindness.

6. X linked inheritance • X-linked Dominant disorders • Show a pattern of transmission of the mutant phenotype from an affected male parent to all female offspring, and from an affected heterozygous female parent to 50% of all offspring. • Examples of X-linked dominant disorders include Vitamin D resistant rickets and fragile X syndromes

7. Reciprocal Crosses • X linkage is often determined by carrying out a reciprocal cross. • A reciprocal cross is one of a pair of matings in which two opposite sexes are coupled with each of two different genotypes and mated in opposite combinations. • For example, a female of a certain genotype A is first crossed with a male of genotype B. Then, in the reciprocal cross, a female of genotype B is crossed with a male of genotype A. • If the gene is autosomal it will not matter which parent has which phenotype; all of the offspring will show the dominant phenotype we see in F1 for any monohybrid cross. • If it is X-linked, the offspring in F1 or F2 will be different from that expected in a cross involving autosomal genes.

8. Example of a reciprocal cross • Gene which determines eye colour in Drosophila is X-linked. Wild type flies have red eyes. • XR – and Xr – white. • Using purebreeding parental stocks: • Cross 1: • Red eyed female X white eyed male • XRXR X XrY • Gametes all XR Gametes ½ Xr & ½ Y • All female offspring XRXr – red eyed • All male offspring XRY – red eyed • Cross 2: • White eyed female X red eyed male • XrXr X XRY • Gametes all XR Gametes ½ Xr & ½ Y • All female offspring XRXr – red eyed • All male offspring XrY – white eyed • First cross tells us that red is dominant phenotype • Second cross results are not consistent with autosomal inheritance, indicating X-linkage.

9. Y linked inheritance • There are far fewer Y-linked than X-linked genetic disorders • This is not surprising given that the Y chromosome is smaller and has many less genes than the X chromosome. • Y-linked inheritance shows a pattern of transmission of the mutant phenotype from father to son, and it is never observed in females. • An example of a Y linked phenotypic trait is hairy ears.

10. Sex limited inheritance • Y-linked inheritance is often confused with sex-limited inheritance. • Sex-limited traits can only occur in one sex because the feature affected is unique to that sex. • For example, premature baldness is an autosomal dominant trait, but presumably as a result of female sex hormones, the condition is rarely expressed in the female, and then usually only after menopause.

11. X-inactivation • During the growth and development of females’ cells, one X chromosome is inactivated in each body cell. • The inactivated X chromosome is visible in a female’s cells as a Barr body. • Which of the two X chromosomes becomes inactive in a cell is a matter of chance, therefore heterozygous females express different alleles in different cells. • This is generally not noticeable in the phenotype – for example a woman heterozygous for the recessive condition haemophilia A will produce sufficient clotting factor VIII. • Tortoise shell cats are an example where X inactivation is visible in the phenotype as one of the genes which controls coat colour is sex-linked.

12. Barr body X-inactivation • One of the genes that controls coat colour in cats is sex-linked. • It has alternative alleles Xo (orange) and Xb (black) • Patches of cells in which the Xo are inactivated will produce dark fur. • Patches of cells in which the Xb is inactivated will produce orange fur.

13. Pedigree Analysis • Is the technique of looking through a family tree (of humans or other organisms) for the occurrence of a particular characteristic in one family over a number of generations. • Can be used to determine the likely mode of inheritance: • Autosomal dominant • Autosomal recessive • X-linked dominant • X-linked recessive • When looking at pedigrees, incomplete penetrance is occasionally observed. • Incomplete penetrance describes the situation where a proportion of a population with a particular genotype does not show the expected phenotype. • Complete penetrance of a phenotype means that all individuals with a particular genotype will show the affected phenotype.

14. Symbols used in drawing pedigrees

15. Autosomal Dominant Pattern • An idealised pattern of inheritance of an autosomal dominant trait includes the following features: • both males and females can be affected • all affected individuals have at least one affected parent • transmission can be from fathers to daughters and sons, or from mothers to daughters and sons • once the trait disappears from a branch of the pedigree, it does not reappear • in a large sample, approximately equal numbers of each sex will be affected. Examples include: • Huntington disease • Achondroplasia (a form of dwarfism) • Familial form of Alzheimer disease • Defective enamel of the teeth • Neurofibromatosis (the ‘Elephant man’ disease)

16. Autosomal Recessive Pattern • An idealised pattern of inheritance of an autosomal recessive trait includes the following features: • both males and females can be affected • two unaffected parents can have an affected child • all the children of two persons with the condition must also show the condition • the trait may disappear from a branch of the pedigree, but reappear in later generations • over a large number of pedigrees, there are approximately equal numbers of affected females and males. Examples include: • Albinism • Cystic fibrosis • Thalassaemia • Tay-Sachs disease • Phenylketonuria • Red hair colour

17. X linked Dominant Pattern • An idealised pattern of inheritance of an X-linked dominant trait includes the following features: • a male with the trait passes it on to all his daughters and none of his sons • a female with the trait may pass it on to both her daughters and her sons • every affected person has at least one parent with the trait • if the trait disappears from a branch of the pedigree, it does not reappear • over a large number of pedigrees, there are more affected females than males Examples include: • Vitamin D resistant rickets • Incontinentia pigmenti, a rare disorder that results in the death of affected males before birth

18. X linked Recessive Pattern • An idealised pattern of inheritance of an X-linked recessive trait includes the following features: • all the sons of a female with the trait are affected • all the daughters of a male with the trait will be carriers of the trait and will not show the trait; the trait can appear in their sons • none of the sons of a male with the trait and an unaffected female will show the trait, unless the mother is a carrier • all children of two individuals with the trait will also show the trait • in a large sample, more males than females show the trait. Examples include: • Ichthyosis, an inherited skin disorder • One form of red–green colour-blindness • One form of severe combined immunodeficiency disease • Haemophilia • Fragile X syndrome • Duchenne muscular dystrophy

19. Is the condition observed in each generation of a family in which it occurs? NO YES Is the condition mainly in males? If daughters have the condition does their father also have it? Do males with the condition who mate with a normal female have all daughters, but no sons with the condition? Do only males have condition, passing it from father to son? ON NO YES NO YES YES Autosomal recessive Autosomal dominant Y linkage Sex-linked recessive Sex-linked dominant