1 17 Feb 1890 London, England 29 July 1962 Adelaide, Australia 21 Dec 1889 Melrose, MA 3 March 1988 Madison, WI Sewall WrightR. A. Fisher

2 1890: Born in East Finchley, London. 1909: Student at Gonville and Caius College, Cambridge. 1919: Statistician at Rothamsted Experimental Station. 1933: Chair of Eugenics at University College, London. 1943: Balfour Professor of Genetics, Cambridge University. 1957: President of Gonville and Caius College. 1962: Died Adelaide, South Australia. R. A. Fisher

3 1929, Elected a Fellow of the Royal Society 1938, Royal Medal of the Society 1948, Darwin Medal of the Royal Society:... in recognition of his distinguished contributions to the theory of natural selection. 1955, Copley Medal of the Royal Society:... in recognition of his numerous and distinguished contributions to developing the theory and application of statistics for making quantitative a vast field of biology. R. A. Fisher

4 1889, Born in Melrose Massachusetts 1911, Student, Cold Spring Harbor, summer 1915, PhD Harvard University , Researcher, USDA , Professor, University of Chicago Fulbright Professor, University of Edinburgh, , Emeritus Professor, University of Wisconsin 1988, Died in Madison, Wisconsin S. Wright

5 1947,Weldon Medal of the Royal Society 1947, Elliott Award of National Academy of Sciences 1956, Kimber Award of National Academy of Sciences 1966, National Medal of Science 1980, Medal of the Royal Society of London 1984, Balzan Prize Lewis Prize of the American Philosophical Society. S. Wright

6 Sickle Cell Disease A heritable blood disorder that affects red blood cells. – The sickle cell allele changes the normal hemoglobin A into hemoglobin S (the “S” stands for Sickle)  hemoglobin: the oxygen carrying molecule in red blood cells – red blood cells that contain mostly hemoglobin S become stiff and sickle shaped rather than the normal soft round cells – sickle cells have difficulty passing through small blood vessels and cause blockages – blockages allow less blood to reach that part of the body and result in tissue damage.

7 Complications include – anemia – heart failure – increased susceptibility to pneumonia – kidney failure – enlargement of the spleen Many people with sickle cell disease do not survive long enough or are not healthy enough to have children Sickle Cell Disease

8 Most common in West and Central Africa where as many as 25% of the people have sickle cell trait and 1-2% of all babies are born with a form of Sickle Cell disease. – In the U.S. with an estimated population of 300 million, about 1,000 babies are born with sickle cell disease each year. – In Nigeria, with an estimated population of ~90 million, 45,000-90,000 babies are born with sickle cell disease each year. – Frequency of S hemoglobin allele is higher in Nigeria than in the U.S. Sickle Cell Disease

9 Population Genetics of SCD in the U.S. Homozygotes for the normal hemoglobin A gene (AA) – Do NOT suffer from SCD – Viability, W AA = 1.00 Homozygotes for the sickle cell form, hemoglobin S (aa) – suffer from SCD – Viability, W aa = 1 – s, where ‘s’ is the selection coefficent. Heterozygotes (Aa) – Do not suffer from SCD – Viability, W Aa = 1.00 SCD is a Recessive Genetic Disease, because the viability of the heterozygote equals that of the normal homozygote.

10 Population Genetics of SCD in U.S. AA AaAa aa PhenotypesGenotypes Viability Fitness W AA W aa WAaWAa = 1.0 = 0.1 Normal SCD

11 s, selection coefficient of an allele Natural Selection ~ s Random Genetic Drift Population Size Threshold N e = 500 Genes with s in this range are effectively neutral have a history determined largely by RGD Alleles with s in this range have a history determined largely by natural selection +/-

Natural Selection Random Genetic Drift Population Size Threshold N e > >1,000,000 Alleles with s in this range have an evolutionary history determined largely by natural selection. Essentially ALL alleles fall in this region. +/- R. A. Fisher’s World View s, selection coefficient of an allele Domain of Natural Selection is very large. Domain of of RGD is very small.

Natural Selection Random Genetic Drift Population Size Threshold N e = 50 Alleles with s in this range are effectively neutral and have an evolutionary history determined largely by RGD +/- S. Wright’s World View s, selection coefficient of an allele For a neutral allele, s = 0, and it does not experience natural selection

Natural Selection Random Genetic Drift Population Size Threshold N e = 50 Alleles with s in this range are effectively neutral and have an evolutionary history determined largely by RGD +/- S. Wright’s World View s, selection coefficient of an allele Domain of Natural Selection is comparable to Domain of of RGD.

15 Interaction of the three evolutionary forces: Mutation, Selection, and RGD Only naive theories about evolution assume that Natural Selection leads a population to achieve an optimal level of adaptation. Because Mutation introduces harmful alleles into populations and because they can become fixed by Random Genetic Drift, Natural Selection simply cannot produce the best of all possible worlds.