1. Medical Genetics & Genomics Windsor University School of Medicine
Guri Tzivion, PhD
Extension 506
BCHM 590: Summer 2015
Windsor University School of Medicine

2. BCHM 590 MD2 Genetics Class 16 Genetics of Organisms & Populations 1
BCHM 590 MD2 Genetics Class 16 Genetics of Organisms & Populations 1. Quantitative genetics and multifactorial traits

3. Multifactorial Traits

4. Extending Mendelian genetics
Mendel worked with a simple system
Peas are genetically simple
The traits he chose to analyze are controlled by a single gene
Each gene he analyzed had only 2 alleles, 1 of which was completely dominant to the other
The relationship between genotype & phenotype is rarely that simple and there are many exceptions to Mendel’s rules and findings

5. Single-gene disorders
Single-gene disorders are caused by individual mutant genes, and frequently show a simple pattern of inheritance
There are approximately 6000 known single-gene disorders. Individually they are rare, affecting usually from 1 in 10,000, to 1 in 100,000, however, combined, affect ~1% of the population
Certain single-gene disorders depend on an environmental trigger before the phenotype is expressed, e.g., lactose and alcohol intolerance
Single gene disorders follow Mendelian patterns of inheritance, thus, affected families are at much higher risk of developing the condition than the population as a whole

6. Polygenic & Multifactorial Disorders
Polygenic traits are controlled by two or more genes
Multifactorial traits/disorders are polygenic traits with an environmental component

7. Multifactorial disorders
Defined as conditions or a predisposition to a condition that involves the combination of small gene variations and environmental factors
Although multifactorial disorders tend to recur in families, they do NOT show the Mendelian pattern of inheritance
Many cancer types are examples of common multifactorial disorders

8. Examples of polygenic and multifactorial disorders
Autism & epilepsy
Dibetes mellitus & Glaucoma
Hypertension, Ischemic heart disease & Ischemic stroke
Manic depression & Schizophernia
Multiple sclerosis & Parkinson disease
Crohn disease (inflammatory bowel disease and ulcerative colitis), Asthma, Psoriasis & Rheumatoid arthritis
Congenital malformations, for example, neural tube defects, congenital dislocation of the hip (CDH), cleft lip and palate and congenital heart disease.

9. Congenital abnormalities and dysmorhpic syndromes
Congenital abnormalities are apparent at birth in 1 in 40 of all newborn infants.
They account for 20-25% of all deaths occurring in the prenatal period and in childhood up to the age of 10 years.
Congenital abnormalities can be caused by chromosome imbalance, single gene defects, multifactorial inheritance or non genetic factors. Most isolated malformations show multifactorial inheritance, whereas most dysplasia have a single gene etiology.
Many congenital malformations, including cleft lip plate, congenital heart defects, show etiological heterogeneity.
Many environmental agents have been shown to have a teratogenic effect and increase the chance of malformations.

10. How evidence is gathered for genetic factors in complex diseases:
Familial risks: what is the incidence of a disorder in relatives compared with the incidence in the general population?
Twin studies: what is the incidence in monozygotic compared with dizygotic twins?
Adoption studies: what is the incidence in adopted children of the disorders which their parent had?
Population and Migration studies: what is the incidence in people from a particular ancestry group when they move to a different geographical area?)
Evidence from these types of studies can estimate the heritability of a condition - the proportion of the aetiology ascribed to genetic factors rather than environmental factors

11. Types of multifactorial inheritance

12. Incomplete & co-dominance
Heterozygotes show an intermediate phenotype
RR = red flowers
rr = white flowers
Rr = pink flowers
make 50% less color

13. Incomplete dominance P F1 100% 1:2:1 F2 X true-breeding red flowers
white flowers P
100% pink flowers F1
generation
(hybrids)
100%
self-pollinate
25%
red
50%
pink
25%
white
1:2:1 F2
generation

14. Co-dominance
Alleles affect the phenotype in separate, distinguishable ways
ABO blood groups: 3 alleles
IA, IB, i
both IA & IB are dominant to i allele
IA & IB alleles are co-dominant to each other
Determine the presences of oligosaccharides on the surface of red blood cells

15. Blood types IA IA IA i type A IB IB IB i type B IA IB type AB i i
genotype
phenotype
status
IA IA IA i
type A
type A oligosaccharides on surface of RBC __
IB IB IB i
type B
type B oligosaccharides on surface of RBC
IA IB
type AB
both type A & type B oligosaccharides on surface of RBC
universal recipient
i i
type O
no oligosaccharides on surface of RBC
universal donor

16. Epistasis One gene masks another: coat color in mice pigment (C) or
no pigment (c)
more pigment (black=B)
or less (brown=b)
cc = albino, regardless
of B allele
9:3:3:1 becomes 9:3:4

17. Epistasis in Labrador retrievers
2 genes: E & B
pigment (E) or no pigment (e)
dark pigment color: black (B) brown (b)

18. Polygenic inheritance
Some phenotypes are determined by the additive effects of 2 or more genes on a single character
Phenotypes on a continuum
Examples of human traits:
Skin color
Height
Weight
Eye color
Intelligence
Some behaviors

19. Monogenic traits, e.g., pituitary dwarfism
Qualitative Traits (the phenotypes fall into different and distinct categories).
Monogenic traits, e.g., pituitary dwarfism
120 cm cm
aa AA or Aa
Height of individuals with pituitary dwarfism
& of normal population

20. Monogenic traits, e.g., Phenylketonuria (PKU)
0~5% %~50% %
aa Aa AA
PAH (phenylalanine hydroxylase) activity of
PKU, carrier & normal individuals

21. Quantitative Traits, e.g., height

22. Quantitative Traits Polygenic traits Gaussian (normal) distribution
The bell-shaped curve
Height (cm) 80 70 60 50 40 30 20 10
Variability

24. Pleiotropy
Pleiotropy: when one gene affects more than one seemingly unrelated phenotypic character.
Most genes are pleiotropic, for example, dwarfism, phenylketonuria and sickle cell anemia.
The genes that we have covered so far affect only one phenotypic character, but most genes are pleiotropic

25. Sex-linked traits
In humans & other mammals, there are 2 sex chromosomes: X & Y
2 X chromosomes develops as a female: XX
Redundancy
X & Y chromosome develops as a male: XY
No or small redundancy

26. Genes on sex chromosomes
Y chromosome
SRY: sex-determining region
Master regulator for maleness
Turns on genes for production of male hormones (pleiotropy)
X chromosome
Other traits beyond sex determination
Hemophilia
Duchenne muscular dystrophy
Color-blindness
Duchenne muscular dystrophy affects one in 3,500 males born in the United States.
Affected individuals rarely live past their early 20s.
This disorder is due to the absence of an X-linked gene for a key muscle protein, called dystrophin.
The disease is characterized by a progressive weakening of the muscles and loss of coordination.

27. Human X chromosome Sex-linked traits are usually X-linked
More than 60 diseases have traced to genes on the X chromosome

28. Map of Human Y chromosome?
< 30 genes on Y chromosome
Only few linked diseases: Retinitis Pigmentosa (RPY gene)
SRY

29. Male pattern baldness Sex-influenced trait
Autosomal trait influenced by sex hormones (androgen receptor and other)
age effect as well: onset after 30 years old
Dominant in males & recessive in females

30. X-inactivation Female mammals inherit two X chromosomes
one X becomes inactivated during embryonic development
condenses into a compact object: Barr body

31. X-inactivation & tortoise shell cat
2 different cell lineages in cats

32. Prevalence of dominance
Because an allele is dominant does not mean…
it is better
it is more common
Polydactyly:
dominant allele

33. Polydactyly individuals are born with extra fingers or toes
dominant to the recessive allele for 5 digits
The recessive allele is far more common than the dominant
 399 individuals out of have only 5 digits
 most people are homozygous recessive (aa)

34. Polydactyly individuals are born with extra fingers or toes
dominant to the recessive allele for 5 digits
One of the polydactyl cats at the Ernest Hemingway’s House in Key West, Florida
The recessive allele is far more common than the dominant
399 individuals out of 400 have only 5 digits
most people are homozygous recessive (aa)

35. Hound Dog Taylor

36. Suggestions for Block 1 questions:
Who was Hound Do Taylor:
Crystallographer
Biochemist
Molecular Biologist
Guitarist
Geneticist