1

17 Feb 1890 London, England29 July 1962 Adelaide, Australia

21 Dec 1889 Melrose, MA3 March 1988 Madison, WI

Sewall Wright R. 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 • 1915-1925, Researcher, USDA• 1926-1954, Professor, University of Chicago • 1949-1950 Fulbright Professor, University of Edinburgh, • 1954-88, 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.

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• 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

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• 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

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Population Genetics of SCD in the U.S.• Homozygotes for the normal hemoglobin A gene (AA)

– Do NOT suffer from SCD– Viability, WAA = 1.00

• Homozygotes for the sickle cell form, hemoglobin S (aa)– suffer from SCD– Viability, Waa = 1 – s, where ‘s’ is the selection coefficent.

• Heterozygotes (Aa)– Do not suffer from SCD– Viability, WAa = 1.00

SCD is a Recessive Genetic Disease, because the viability of the heterozygote equals that of the normal homozygote.

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Population Genetics of SCD in U.S.

AA

Aa

aa

Phenotypes GenotypesViabilityFitness

WAA

Waa

WAa

= 1.0

= 1.0

= 0.1

Normal

Normal

SCD

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s, selection coefficientof an allele

0.1000

0.0100

0.0010

0.0001

Natural Selection ~ s

Random Genetic Drift0.00001

Population SizeThresholdNe = 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

+/-

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0.1000

0.0100

0.0010

0.0001

Natural Selection

Random Genetic Drift

0.00001Population Size

Threshold Ne > >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 coefficientof an allele

Domain of Natural Selection

is very large.Domain of

of RGD is very small.

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0.1000

0.0100

0.0010

0.0001

Natural Selection

Random Genetic Drift0.00001

Population SizeThreshold

Ne = 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 coefficientof an allele

For a neutral allele, s = 0,

and it does not experience

natural selection

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0.1000

0.0100

0.0010

0.0001

Natural Selection

Random Genetic Drift0.00001

Population SizeThreshold

Ne = 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 coefficientof an allele

Domain of Natural Selection is comparable to

Domain of of RGD.

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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 intopopulations and because they can become fixed

by Random Genetic Drift, Natural Selection simply cannot produce the

best of all possible worlds.