1. 1 Genetic Disorders Gaia Scerif Room 426, Ext. 67926 gs@psychology.nottingham.ac.uk Office Hours: Thurs 1-3

2. 2 Learning objectives * Why study genetic disorders? Disorders following Mendelian Laws of InheritanceDisorders following Mendelian Laws of Inheritance Beyond Mendelian LawsBeyond Mendelian Laws

3. 3 Why study genetic disorders? Clinical Practice: The Human Genome Project has increased the probability of identifying genetic origins for an increasing number of disorders previously defined solely in terms of their symptoms Official site of the Human Genome Project: http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosom e/diseaseindex.shtml Online Mendelian Inheritance in Man (OMIM): http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

4. 4 Why study genetic disorders? Theory: For a number of researchers, genetic disorders also provide a unique opportunity: Decreased or absent expression of a gene A, accompanied by a deficit in function B => Role of A in implementing B dawn of cognitive genetics The 21 st century as the “dawn of cognitive genetics” (Pinker, 2001, p. 466)

5. 5 Disorders and Mendelian Laws Huntington’s Disease (HD): 1 in 10,000-20,000 individuals Characterised by involuntary movements, personality changes, forgetfulness Due to progressive damage of basal ganglia and cortex = Autosomal dominant disorder (chr. 4) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM Hhhh Parents HhHhhh Offspring Gametes H h hh AffectedUnaffected

6. 6 Disorders and Mendelian Laws Phenylketonuria (PKU): 1 in 10,000 individuals Used to be responsible for 1% of all hospitalised cases of learning disability Due to dysfunction in pathway producing the amino acid tyrosine = Autosomal recessive disorder (chr. 12) http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=261600 Pp Parents PPPppp Offspring Gametes P p Pp Unaffected Carriers Affected

7. 7 Beyond Mendel 1. Sporadic mutations. For example: Abnormalities in chromosomal numbers Deletions (single genes, multiple genes) 2. X-linked disorders Changes in the number of X chromosomes Gene dysfunctions for single genes on the X chromosome 3. Complex traits Schizophrenia?

8. 8 1. Sporadic Changes Abnormalities in chromosomal numbers (due to errors in segregation of alleles when gametes are produced) E.g., Down’s syndrome: Approximately 1 in 1,000 Prevalence increases depending on age of parents Majority of cases due to trisomy of chromosome 21 Some symptoms (e.g., facial dysmorphology) evident from birth, while others (short stature, learning difficulties) only become apparent later in life. In general, IQ on average 55, but great variability in general performance and cognitive profile http://www.downs-syndrome.org.uk/

9. 9 1. Sporadic Changes Deletions (due to errors in replication of DNA during gamete formation) E.g., Williams syndrome: Approximately 1 in 20,000 Prevalence does not increase depending on age of parents Due to a microdeletion on chromosome 7 Some symptoms (e.g., facial dysmorphology) In general, IQ on average 50-70, but great variability in general performance and cognitive profile Uneven profile of cognitive abilities has been of great interest: dissociation between language and general cognitive ability? http://www.williams-syndrome.org.uk/

10. 10 2. X-linked Genes Sex chromosomes are inherited differently for males (XY) and females (XX), so detecting that a gene is located on the X chromosome is easier Colour-blindness: first reported case of human X linkage: ccC ccC c CC c Cc C C CC ccC C C Father Mother Daughter Son

11. 11 2. X-linked Disorders Changes in the number of sex chromosomes: X0 (women with Turner syndrome): 1 in 2,500 births Physical characteristics: E.g., Short stature, infertility Verbal IQ generally normal, but performance IQ can be lower http://gslc.genetics.utah.edu/units/disorders/ka ryotype/turnersyndrome.cfm http://www.tss.org.uk/

12. 12 2. X-linked Disorders Changes in the number of sex chromosomes: X(+)XY (men with Kleinefelter syndrome): 1 in 750 male births Main problems due to hormonal imbalances (treatable), lower than average IQ, speech and language difficulties http://klinefeltersyndrome.org/

13. 13 2. X-linked Disorders Gene dysfunctions for single genes on the X chromosome: Fragile X syndrome: 1 in 2000-4,000 boys, 1 in 6,000 girls Complex profile of relative cognitive strengths (e.g., receptive language) and difficulties (e.g., visuo-spatial cognition and attention) http://www.fraxa.org/ http://www.fragilex.org.uk/page3.htm

14. 14 3. Complex Traits For complex traits, a behaviour genetics approach is necessary. Twins as a way of testing whether shared genetic and environmental factors account for risk Schizophrenia Nearly 1 in 100 people No simple inheritance pattern Familial (morbidity risk) Adoption studies: 5% rate of schizophrenia for biological parents of schizophrenic adoptees (Kety et al., 1994) Strong genetic influence, but… 1% 9% 17% 48% 4% Modified from Gottesman (1991)

15. 15 Summary * Why study genetic disorders? Practice and theory Disorders following Mendelian lawsDisorders following Mendelian laws Autosomal dominant (HD)Autosomal dominant (HD) Autosomal recessive (PKU)Autosomal recessive (PKU) Beyond Mendelian LawsBeyond Mendelian Laws Sporadic disorders (DS, WS)Sporadic disorders (DS, WS) X-linked disorders (Turner, Kleinefelter, Fragile X syndrome)X-linked disorders (Turner, Kleinefelter, Fragile X syndrome) Complex traits (schizophrenia, mood disorders)Complex traits (schizophrenia, mood disorders)