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Pedigrees – Important Points are in BLUE • • • • Analysis of inheritance in human families Typically small number of offspring -> Mendelian ratios rarely observed Allow inferences concerning genotypes and predictions concerning phenotypes of offspring (genetic counseling) Studying human genetics • You cannot make humans of different types breed together • Pedigree charts offer an ethical way of studying human genetics • Today genetic engineering has new tools to offer doctors studying genetic diseases • A genetic counselor will still use pedigree charts to help determine the distribution of a disease in an affected family Symbols used in pedigree charts • Normal male • Affected male • Normal female • Affected female • Marriage • Arranged Oldest to youngest – L to R Most common signs and symbols used in pedigree analysis Organizing the pedigree chart – Generations are identified by Roman numerals I II III IV Organizing the pedigree chart • Individuals in each generation are identified by Roman numerals numbered from the left • Therefore the affected individuals are II3, IV2 and IV3 I II III IV Categories of inheritance • • • • • • Autosomal (non sex-linked) recessive Autosomal dominant X-linked recessive X-linked dominant Y-linked Organelle Pedigree analysis: case 1 P/p pp PP or Pp PP or Pp P/p pp PP or Pp • Two children, one of each sex, show the trait but trait was not shown in the parents • Conclusions: – – – – must be autosomal recessive trait (example: PKU) parents must be heterozygous (Pp) 2/3 chance for each unafflicted child to be heterozygous (Pp) 1/3 chance for each unafflicted child to be homozygous (PP) Autosomal recessive inheritance in pedigrees • Trait is rare in pedigree • Trait often skips generations (hidden in heterozygous carriers) • Trait affects males and females equally Most common ones • Cystic fibrosis • Sickle cell anemia • Phenylketonuria (PKU) • Tay-Sachs disease Pedigrees: Case 2 A/a a/a A/a a/a a/a a/a A/a A/a a/a a/a a/a a/a A/a a/a a/a A/a a/a A/a a/a Autosomal dominant disorders • Trait is common in the pedigree • Trait is found in every generation • Affected individuals transmit the trait to ~1/2 of their children (regardless of sex) (Note: In fact, in some AD diseases the homozygous genotype is incompatible with life) Typical pedigree for AD disorder A/a a/a A/a a/a a/a a/a A/a A/a a/a a/a a/a a/a A/a a/a a/a A/a a/a A/a a/a Autosomal dominant traits There are few autosomal dominant human diseases (why?), but some rare traits have this inheritance pattern ex. achondroplasia (a sketelal disorder causing dwarfism) Huntington’s disease: an example of AD disorder - Half the people in the Venezuelan village of Barranquitas are affected - A large-scale pedigree analysis was conducted including 10,000 people - Example for one particular family: X-linked recessive disorders • Trait is rare in pedigree • Trait skips generations • Affected fathers DO NOT pass to their sons, • Males are more often affected than females ex. Hemophilia, ColorBlindness Pedigree of an X-linked recessive disorder Father affected Son non affected 1/2 grandsons affected Daugther carrier Hemophilia: an example of X-linked recessive disorder Partial pedigree analysis of hemophilia in royal families of Europe Only males develop the disease! Partial pedigree analysis of hemophilia in royal families of Europe Spontaneous mutation gave rise to defective allele of Factor VIII gene (XfXF) X fY XfXF X fY XfXF XfXF X fX F XfXF XfY X fY X fY X fY XfXF X fY X fY Is it possible that the present British family still harbors the recessive allele? X fY X fY Partial pedigree analysis of hemophilia in royal families of Europe Spontaneous mutation gave rise to defective allele of Factor VIII gene (XfXF) X fY XfXF XfXF ? XfXF\? X fY XfXF XfXF X fX F XfXF XfY X fY X fY X fY Must be XFY, even if mother was XfXF (otherwise he would be sick) so Xf allele was lost in this branch of the family XfXF X fY X fY X fY X fY X-linked dominant disorders • Trait is common in pedigree • Affected fathers pass to ALL of their daughters • Males and females are equally likely to be affected • X-linked dominant diseases are extremely unusual • Often, they are lethal (before birth) in males and only seen in females ex. incontinentia pigmenti (skin lesions) ex. X-linked rickets (bone lesions) Case 4: X-linked dominant disorders Pedigree Analysis in real life: complications Incomplete Penetrance of autosomal dominant traits => not everyone with genotype expresses trait at all Ex. Breast cancer genes BRCA-1 and BRCA-2 & many “genetic tendencies” for human diseases Pedigree Analysis in real life Remember: • dominant traits may be rare in population • recessive traits may be common in population • alleles may come into the pedigree from 2 sources • mutation happens • often traits are more complex • affected by environment & other genes