Genetics: A Conceptual Approach CHAPTER 6 Pedigree Analysis, Applications, and Genetic Testing

Megan, a 5-year-old with Hutchison–Gilford progeria syndrome Megan, a 5-year-old with Hutchison–Gilford progeria syndrome. Today, researchers seek to understand aging from the study of children with this rare autosomal dominant disorder that causes premature aging. [Courtesy of John Hurley for Progeria Research Foundation (progeriaresearch.org).]

6.1 Hutchinson–Gilford progeria syndrome is caused by mutations in the lamin A gene, which encodes the lamin A nuclear protein. A structural model of the lamin A protein. [Courtesy of the RCSB PDB (www.pdb.org).]

PEDIGREE ANALYSIS pedigree analysis is a scrutiny (IVESTIGATION) of records of matings pedigrees use standard sets of symbols to depict family trees and lineages (ancestry) pedigrees provide concise and accurate records of families pedigrees are helpful in following and diagnosing heritable traits (for example, diseases and medical conditions) by describing patterns of inheritance - pedigrees are useful in mapping (locating and isolating) genes “responsible” for certain traits

PEDIGREE CONSTRUCTION - use standard set of symbols - one generation per row (oldest at the top) - siblings are shown in order of birth (from left to right) - generations are given Roman numerals (I, II, III, IV, etc) - individuals within a generation (row) are given Arabic numerals (1, 2, 3, 4, etc)

6.2 Standard symbols are used in pedigrees.

6.3a Waardenburg syndrome is (a) inherited as an autosomal dominant trait. The proband (P) is the person from whom this pedigree is initiated. [Photograph courtesy of Guy Rowland.]

ANALYZING PEDIGREES - trial and error: consider one pattern of inheritance at a time for each mating in the pedigree and try to find evidence against it; repeat for each pattern of inheritance, for example, autosomal recessive or dominant, X-linked recessive or dominant, etc - patterns of inheritance follow Mendelian rules; Mendelian ratios are rarely observed - assumption: for rare traits unaffected people entering into a family pedigree (for example, by marriage) are considered homozygous normal - result: pedigrees can frequently rule out, but not necessarily prove, a certain pattern of inheritance

6.4 Autosomal recessive traits normally appear with equal frequency in both sexes and seem to skip generations.

Autosomal recessive I II III IV - the trait is found equally in both males and females - affected individuals usually have unaffected parents - the pattern of inheritance is often horizontal with several generations of unaffected individuals, but then several siblings in one generation are affected

6.5 Autosomal dominant traits normally appear with equal frequency in both sexes and do not skip generations.

Autosomal dominant I II III IV - the trait is found equally in both males and females - every affected individual has at least one affected parent - trait shows vertical pattern of inheritance, that is affected males and females are observed in each generation

The human pseudoachondroplasia phenotype is determined by a dominant allele D, that interferes with bone growth during development

The age of onset of Huntington disease

6.7 X-linked recessive traits appear more often in males than in females and are not passed from father to son.

X-linked recessive I II III IV - more males than females are affected - all the sons of an affected mother will be affected - half the sons of a carrier mother will be affected - all daughters of carrier mothers will be normal, but half will be carriers - affected males do not transmit the trait to their sons - trait often skips a generation

6. 8 Classic hemophilia is inherited as an X-linked recessive trait 6.8 Classic hemophilia is inherited as an X-linked recessive trait. This pedigree is of hemophilia in the royal families of Europe.

6. 9 X-linked dominant traits affect both males and females 6.9 X-linked dominant traits affect both males and females. An affected male must have an affected mother.

X-linked dominant I II III IV - trait observed in both males and females - affected males ALWAYS transmit the trait to their daughters, but to NONE of their sons - affected females will transmit the trait to both sons and daughters - trait does not skip generation

6.10 Y-linked traits appear only in males and are passed from a father to all his sons.

Y-linked I II III IV - only males are affected - the trait is passed from an affected father to all of his sons

Mitochondrial inheritance II III IV - both males and females are affected - the trait is passed from an affected mother to all her progeny - affected males do not transmit the trait to any of their progeny

6. 11a Monozygotic twins (a) are identical 6.11a Monozygotic twins (a) are identical. [Part a: Joe Carini/Index Stock Imagery/PictureQuest.]

6. 11b Monozygotic twins (b) are nonidentical 6.11b Monozygotic twins (b) are nonidentical. [Part b: Courtesy of Randi Rossignol.]

6.12 Older women tend to have more dizygotic twins than do younger women. Relation between the rate of dizygotic twinning and maternal age. [Data from J. Yerushalmy and S. E. Sheeras, Human Biology 12:95ﾐ113, 1940.]