Evolu&on of Disease genes

Evolu&on of Disease genes

Many human diseases are caused by muta1ons in single genes

A synthe&c pathway and associated diseases

Autosomal dominant condi&ons

Dominant Disorders A single mutant gene is sufficient to result in the disease phenotype Haploinsufficiency one func&onal allele is insufficient to get the job done Malfunc&on faulty protein is produced and interferes with the wildtype allele s func&on

How do dominant disorders persist? If the condi&on is dominant, then the phenotype is always expressed can t hide within heterozygotes How are these not all removed by natural selec&on? 1. Not all disorders affect the ability to have children (e.g. blindness) 2. Some disorders only manifest themselves in later life, aper the bearer has already had children e.g., Hun&ngton s Disease has late- life onset

Recessive condi&ons Caused by inheritance of two mutated versions of gene The phenotype is the result of the absence of func&onal gene product Albinism is caused by inheri&ng a mutant pigment gene from mother and from father

Inheritance of hæmophilia in the European Royal Family

Hapsburg Lip

Inbreeding increases the chance of having progeny that are homozygous for a rare recessive trait

Homozygous recessives from inbreeding

Increase in recessive gene&c disorders due to inbreeding Frequency of first- cousin marriages for parents of children showing several recessive disorders compared to frequency of first- cousin marriages for families in general

Effect of the degree of dominance in a diploid on the equilibrium frequency of a recessive lethal allele h = degree of dominance. If the deleterious allele is completely recessive, then h= 0

Disease resistance Some individuals seem not to get infected by HIV despite risky lifestyle One allele of the Chemokine Receptor 5 (CCR5) gene was found to confer resistance to HIV infec&on

DNA sequence of a part of CCR5 receptor gene showing the loca1on of the 32 nucleo1de dele1on (Δ32) The amino acid sequence is also shown. Since the deleted stretch is not a mul&ple of 3, a frameship muta&on is created resul&ng in altered amino acids downstream from the end of the dele&on. A premature termina&on codon is also created resul&ng in a truncated protein.

HIV entering a human CD4+ T cell HIV cannot enter (or has reduced efficiency) in the absence of func&onal CCR5

CCR5- delta32 selec&on? Is the pacern of CCR5- delta32 allele frequency explained by natural selec&on for protec&ve proper&es? Possibly, but not selec&on for HIV protec&on HIV is too recent in human popula&ons to explain this allele s prevalence CCR5- delta32 has been shown to also confer some resistance to smallpox Smallpox is an old infec&on that was widespread Many people were exposed and this exposure went on for genera&ons Possible spread of this allele due to selec&ve advantage Alterna&vely, this allele might be present simply due to random gene&c drip The same pacern can be explained by neutral processes The protec&ve effects might be just coincidental The explana&on for this allele distribu&on remains unclear

Deadly disease of the nervous system Caused by a recessive allele of HEXA on chr 15 Prevalent in Ashkenazi Jew popula&on 1 in 27 are carriers Many different known muta&ons Gene&c screening & counselling for couples since 1970s Probable founder effect Tay Sachs Disease

Context- dependent advantage of Sickle- Cell Anæmia Heterozygotes Hb A /Hb S have an advantage over wildtype and over double mutants in the presence of malaria The sickle- cell allele Hb S is preserved in malarial regions disease allele

Cys&c Fibrosis Recessive condi&on primarily affec&ng lung and gut epithelium Caused by muta&on in the CFTR gene Most common muta&on is ΔF508 Ireland has the highest frequency of carriers in the world - 1 in 19 Average carrier frequency in people of European descent is 2% (1 in 50) Frequency of the condi&on in Ireland is 1 in 1353 Is there any explana&on for the high incidence in Ireland (& Europe)? Founder effect? (gene&c drip) Selec&on? Lisa Marie Bezzina (CF pa&ent) during 2011 Mdina to Spinola race (89km).

Common disease in Europe and is par&cularly associated with farming cultures Human TB and Bovine TB are caused by different bacteria, but both may infect humans Carriers of the CFTR ΔF508 allele are resistant to TB The epidemiology, evolu&onary analysis, and clinical studies all support the hypothesis that CFTR ΔF508 has been retained due to its protec&ve proper&es against TB Current best hypothesis is that high frequency of CF carriers in Ireland is a result of selec&on Tuberculosis

Other bits and pieces Some alleles confer an increased risk of developing a par&cular condi&on, but are not determinis&c Type 2 diabetes gene&c and lifestyle risk factors Some similar diseases are caused by different genes (gene&c heterogeneity, e.g. hearing loss) Muta&ons in some genes can lead to different diseases (pleiotropic effects) Some diseases are quan&ta&ve caused by alleles in mul&ple genes Some rela&vely common condi&ons (e.g. schizophrenia or au&sm) are caused by individually rare muta&ons in several different genes. Apparent paradox (common disease, rare variant??) resolved as common disease, rare variants Schizophrenia (red) Au&sm (blue) Both (black)