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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
Recommended