Lecture 3 - Alleles, Genotypes, Phenotypes PDF

BY450 Fundamentals of Genetics & Evolution Alleles, Genotypes, Phenotypes Andy Overall  Alleles An allele is a variant of a gene/locus. Genes/loci can vary in a number of different ways. Allele A...

BY450 Fundamentals of Genetics & Evolution Alleles, Genotypes, Phenotypes Andy Overall  Alleles An allele is a variant of a gene/locus. Genes/loci can vary in a number of different ways. Allele A Allele B Gene X  Alleles An allele is a variant of a gene/locus. Genes/loci can vary in a number of different ways. Gene X: AA AB 2 Alleles, 3 Genotypes BB  Alleles CGATCTGATATGCC Allele A CGATCTAATATGCC Allele B Gene X The difference between the two genes could be as small as a single nucleotide difference (Single Nucleotide Polymorphism)… CGATCTGATATGCC Allele A CGATCTGATATGCC CGATCTGATATGCC Allele B Gene X Or as large as an entire gene duplication; and many things in between. - ATC AT T GGT GTT - - ATC ATC TTT GGT GTT - CTT deleted from this sequence  Wild type F508 allele (c) (normal) allele (C) - ATC AT T GGT GTT - - ATC ATC TTT GGT GTT - CTT deleted from this sequence  Wild type F508 allele (c) (normal) allele (C) - ATC AT T GGT GTT – - ATC ATC TTT GGT GTT – Iso Iso Gly Val Iso Iso Phe Gly Val Genotype: Cc Phenotype: Normal (carrier)  Chromosome Sequence of Amino acid 7 nucleotides in sequence of CFTR gene CFTR protein Isoleucine 506 Isoleucine 507 Deleted in many patients Phenylalanine 508 with cystic fibrosis Glycine 509 Valine 510 Cystic fibrosis gene resides on chromosome 7 and normally gives rise to a pro-tein called the cystic fibrosis transmembrane conductace regulator (CFTR). The defect that most often leads to the disease is the deletion of three nucleotides from the gene (red letters): this alteration known as F508 mutation results in the loss of one amino acid – phenylalanine at position 508 – in the CFTR protein. Phenylalanine is lost because the protein-making machinery of the cell now sees ATT (an alternative way to encode isoleucine) at the gene region coding for the protein’s 507th amino acid, followed by GGT sequence for the glycine that normally follows phenylalanine. Male Femal e Offsprin g  Male Femal e C c C C Gamete C c C s Offsprin g CC cC Why does having the mutation not affect the phenotype?  Autosomal Recessive Mutations that result in loss of functional gene product eg, insertions, deletions, premature stop codons, frame shift mutations show recessive inheritance. Two copies of the mutation are required to display mutation phenotype.  Male Femal e C c C c Gamete C c C c s Offsprin g CC cC Cc cc Risk of an affected offspring is 25%  Pedigrees – autosomal recessive I 1 2 II 1 2 3 4 5 6 III 1 2 3 IV 1 2 3 4 What we see  Pedigrees – autosomal recessive I 1 2 II 1 2 3 4 5 6 III 1 2 3 IV 1 2 3 4 What we infer From Strachan & Lucassen:  Pedigrees – autosomal dominant Disorders result from mutations which often manifest in either gene products with novel functions or genes expressed in an unregulated fashion.  R/- R/- R/- R/- R/- Pedigree showing dominant inheritance: the inheritance of the mutation (R) corresponds with the inheritance of the disease phenotype. Pedigrees – sex linked Pedigrees – sex linked Pedigrees – sex linked  Pedigrees – sex linked X-chromosome inactivation (Lyonization). Females can inherit disorder genotype, but not express condition – reduced penetrance. Features that Support the Single-Gene or Mendelian Patterns of Inheritance Charles II (1665-1700)- the last king of the Spanish Habsburg dynasty. Physically disabled, mentally retarded, disfigured and impotent. Why? Habsburg lands in Green, around 1547* *https://en.wikipedia.org/wiki/House_of_Habsburg#/media/File:Habsburg_Map_1547.jpg 11 consanguineous marriages  Calculate inbreeding coefficient (f) I 1 2 II 1 2 3 4 5 6 III Consanguineous 1 2 3 union IV “Inbred” offspring 1 2 3 4 “Inbred” individuals are more likely to be homozygous for deleterious, recessive  Calculate inbreeding coefficient (f) I A B C D 1 2 A A II 1 2 3 4 5 6 The “A” allele may be III A A very rare in the 1 2 3 population (~1/10,000), but 1st cousins have a 1/8 IV A A chance of sharing it. 1 2 3 4  Calculate inbreeding coefficient (f) I A B C D 1 2 Possible inheritance from father: A A II 1 2 3 4 5 6 A A A A A B III 1 2 3 B A IV A A B B 1 2 3 4 Chance that sibs share the “A” allele is ¼.  Calculate inbreeding coefficient (f) A B C D 1/2 1/2 A A 1/2 1/2 A A 1/2 1/2 A A The probability that this individual inherits two great-grandparental ‘A’ alleles = 1/26 = 1/64  Calculate inbreeding coefficient (f) A B C D 1/2 1/2 B B 1/2 1/2 B B 1/2 1/2 B B The probability that this individual inherits two great-grandparental ‘B’ alleles = 1/26 = 1/64  Calculate inbreeding coefficient (f) A B C D 1/2 1/2 C C 1/2 1/2 C C 1/2 1/2 C C The probability that this individual inherits two great-grandparental ‘C’ alleles = 1/26 = 1/64  Calculate inbreeding coefficient (f) A B C D 1/2 1/2 D D 1/2 1/2 D D 1/2 1/2 D D The probability that this individual inherits two great-grandparental ‘D’ alleles = 1/26 = 1/64 The probability that this individual is homozygous for alleles IDENTICAL Maximilian I Mary of Burgundy Joanna I of Castile and Philip I (1478–1506) Aragon (Joanna the mad) (Philip the Handsome / fair) – founder of the Spanish Habsburg dynasty. Third cousins Isabella of Portugal (1503 – Charles I (Holy Roman 1539) Emperor, Charles V), 1500 First cousins - 1558  Anna of Austria (1549 – Philip II (1527– 1580) 1598) Uncle-niece Margaret of Austria (1584 – Philip III (1578–1621) 1611) First cousins once removed Mariana of Austria (1634 – 1696) Philip IV (1605–1665) Uncle-niece Charles II (1661–1700) Infant child mortality: 1527-1661, Spanish royal families had 34 children, 10 (29%) died before 1 year, 17 (50%) before 10 years compared with 20% infantile mortalities in general population.  0.039 0.025 0.101 0.037 0.123 0.123 0.106 0.218 0.139 0.115 0.155 Inbreeding coefficient 0.254 (F)