Human Genetics

PATH5035 / BIOC4835 / BIOL4035

Lecture 1:

History Of Genetics

Concepts of human genetics have influenced

social and political events

Science of human genetics has been

influenced by political forces

Ancient Times (pre 300AD)

Greek Physicians and Philosophers

Observed inherited differences

Developed theoretical concepts

Proposed “eugenic” measures

Hipocrates:

“the semen is produced by the whole body…healthy by healthy parts, sick by sick parts…hence as a rule, baldheaded beget baldheaded, blue eyed-blue eyed—what should hinder that longheaded beget longheaded”

-He noted normal vs abnormal

-He assumed semen was the information carrier

-He distinguished physical vs mental traits

Anaxagoras (500-428 B.C)

His ideas were similar to Hipocaates

Semen contains preformed hair, nails, veins etc

—after all, how could hair grow from non-hair?

He believed that men produced the seed and women the breeding ground

Aristotle

He believed that the male gives the impulse and female the matter (like a carpenter building something from wood)

If the male impact is stronger, a male is born who is like his father; when the female a daughter like

her mother (this is an example of how

preconceived notions can influence observation)

Plato

He believed that people place too much importance on their own likes and dislikes such that they mate with individuals like themselves. He believed they should do the opposite.

“If one with a courageous character is reproduced for many generations, at first it becomes superlatively powerful, but in the end it breaks out into sheer fury and madness. If the character is too full of modest reticence and untinged by valor and audacity, if reproduced for many generations, becomes too dull to respond to the challenges of life and in the end becomes quite incapable of action at all”

In his Eutopia---Eugenics

-women are common property

-children are publicly educated

-best of both sexes should beget children

-inferior children should be abandoned

Democritus

“more people become able by exercise than by

their natural predisposition”

He was the first to discuss “nature vs nurture”

Middle Ages (300BC-1500AD)

• New attitude looking at

natural phenomena from

an empirical point of view

Mercado 1605

The first to suggest that both parents contributed a seed

Maupertuis 1752

He published an account of a 4-generation family with polydactily

• Transmission by father or mother

• Chance couldn’t account for the high frequency of

the trait in the family

Joseph Adams 1814

Published “A treatise on the supposed hereditary properties of disease”

• Recessive vs. dominant

• In families with recessive disease, parents are often related

• Late onset

• Predisposition (incomplete penetrance) with progeny still being at risk

• Age of onset within families had predictive value

• Identical diseases may have different genetic bases

• Inbreeding leads to an increase in genetic disease

• New mutation

• He proposed establishing a registry for genetic diseases

Nasse 1820

First to recognize X-linkage in hemophilia

Only males were affected

Women of these families transmit this tendency from their

fathers to their children, even when they are married to

husbands from other families who are not affected with

this tendency

This tendency never manifests itself in these women

Galton 1865

Biometrics—he statistically compared the likelihood of achievement and success among relatives vs non relatives and noted a strong genetic component

His work began with strong eugenic intentions

Mendel 1865

Did breeding experiments to study inheritance of pea traits

His experiments were presented to Natural Sciences Ass’n in Czech Republic in 1865 but were ignored for 35 years

They were rediscovered by Correns, Tschemak and deVries in 1900

Mendel’s Laws:

Law of uniformity :

• After crossing of two homozygotes of different alleles the progeny of the first filial generation are all identical and heterozygous

Law of segregation:

• Postulated 1:2:1 segregation in intercrosses of heterozygotes and 1:1 segregation in backcrosses of heterozygotes with homozygotes

Law of independence:

• Different segregating traits are transmitted independently

Extraordinary contribution

Examined single traits

Went beyond qualitative statements

Correct biological interpretation and founded concept of “gene”

Galton’s data didn’t agree with Mendel’s gene

theory

Despite Mendel’s “gene” nothing was know

about genetic material

Garrod 1902

He was the first to apply Mendel’s laws to the study of human traits

Alcaptonuria:

-Trait bred true

-Appeared in sibs of unaffected parents with no family

History

-Common first cousin marriages

Mendel offered a reasonable explanation!!!

Early Acheivements in Human Genetics

Hardy and Weinberg 1908

Set out fundamental theorem of population genetics which explains why a dominant gene does not increase in frequency from generation to generation

Developed a variety of methods for twin research

Von Dungern and Hirschfeld 1911

ABO blood groups identified as alternate forms of a single locus

Fisher 1918

He resolved the differences between Galtonists and Mendelians by pointing out the fact that correlations between relatives in metric traits can be explained by the combined action of many individual genes

Vogt 1926

Introduced the concepts of penetrance and expressivity as aspects of variant expression

Avery, McLeod and McCarty 1944

Showed that genetic information is in the DNA

20th Century - Human Genetics,

Eugenics, Politics

Biological scientists were impressed with an all-

persuasive influence of genetic factors on most normal

physical and mental traits as well as on mental

retardation, mental disease, alcoholism, criminality and

various other sociopathies and were convinced that

humans should be concerned about encouraging

breeding between persons with desirable traits and

discouraging the sick, mentally retarded and disabled

from procreation.

Sterilization laws and restrictive immigration

policies were passed in the US and UK.

Sterilization policies were also passed in

Canada.

Galton was a major proponent of these ideas.

USA and UK

Germany “Rassenhygiene”

Associated with ideas of racial superiority and fear of degeneration of the human race by alcoholism, syphilis, feeblemindedness or persons with lower social strata

Most followers of this movement were nationalistic and opposed to the development of an open society that allows individual freedom and democratic participation—an attitude that was shared with a significant segment of the educated classes in Germany

General eugenic ideas divorced from racism and

other nationalistic notions were often espoused by

intellectuals who were concerned about the

biological future of mankind

This provided an environment for a dangerous type

of sociopolitical prejudice: antisemitism—they

warned against contamination of German blood by

foreign, especially Jewish influences

Recognized scientists such as Fisher, Lenz, Rudin and vonVerschuer accepted Nazi leadership and Nazi philosophy, although most of the propaganda for the new racial hygiene was not formulated by scientists

A eugenic sterilization law was passed in 1933 that forced sterilization for illnesses thought to be genetic in origin and this law was hailed by some in the US

Scandinavia

Sterilization laws were also passed in some

Scandinavian countries, but allowed

voluntary rather than forced sterilization

Soviet Union

Eugenics soon clashed with Marxism and

Leninism

We have move passed this dark chapter in our

history, but there is still much discussion

about inheritance of complex traits such as

behavior, IQ and personality

•Tjio &Levan and Ford & Hamerton 1956

–New cytogenetic methods allowed identity of 46 chromosomes

–Discovery of trisomy 21 as cause of Down’s Syndrome

–-intersex states

–Weismann

–Reduction in meiosis

–Different chromosomes

–Sex chromosome abnormalities

–Somatic Cell Genetics

–Tissue culture and amniocentesis led to the introduction of prenatal diagnosis

Cytogenetic Era

Watson and Crick; Wilkins and Franklin 1953

-discovery of the DNA double helix

Molecular Era

James Watson, a research fellow and Francis Crick a graduate student were studying DNA at Cambridge. They worked with physical models.

Maurice Wilkins and Rosalind Franklin were studying DNA at King’s College, London. They used an experimental approach. Franklin, working mostly alone used X-ray diffraction images of DNA to deduce that phosphate molecules were on the outside and that the DNA molecule was a helix

1962 a Nobel prize for physiology/medicine was awarded to Watson, Crick and Wilkins. Franklin had passed away. This prize is only awarded to living recipients and can only be shared by 3. Would Franklin have won the prize if she were alive??

Matthei and Nerenberg 1961

Began solving the 3 letter code of DNA—genetic code

Arber and Smith 1970

Discovered restriction enzymes that cut DNA at specific sequences

Berg and Boyer 1972

Produced the first recombinant DNA molecules

Sanger, Maxam and Gilbert 1977

Published DNA sequencing methods

Genentech 1977

The first genetic engineering company was founded using recombinant DNA methods to make medically important drugs

Somatostatin 1978

Became the first human hormone produced using recombinant DNA technology

Cancer genes 1981

three independent research teams announced the discovery of human oncogenes

James Gusella 1983

demonstration that the Huntington’s disease gene is on chromosome 4

Botstein, White, Skolnick and Davis 1980

Described restriction fragment length polymprphisms (RFLPs) as linkage markers in family studies

Kary Mullis 1985

Published a paper describing the Polymerase Chain Reaction

The Human Genome Project 1988

Began with the goal of determining the entire sequence of

DNA composing human chromosomes

Alec Jeffreys 1989

Coined the term DNA fingerprinting and was the first to use DNA polymorphisms in paternity , immigration, and murder cases

Tsui and Collins 1989

Identified the gene coding for the cystic fibrosis transmembrane protein on chromosome 7 that, when mutated, causes cystic fibrosis.

1990

First gene replacement therapy-T cells of a four-year old girl were exposed outside of her body to retroviruses containing an RNA copy of a normal ADA gene. This allowed her immune

system to begin functioning

1997

Dolly-First successful attempt at animal cloning from an adult cell

1988 - 2000

Human Genome Project completes sequencing the human genome

2007

Nano era

Unsolved problems

Gene regulation

Embryonic development

Immune function

Brain function

Treatment of genetic disease

Ethical dilemmas—the distinction between selective

abortion of a fetus with Down Syndrome and

infanticide of severely malformed newborns