Human Genetics (Learning Objectives) • Recognize Mendel’s contribution to the field of genetics. • Review what you know about a karyotype: autosomes and sex chromosomes. • Understand and define the terms: characteristic, trait, true-breeder, genotype,

phenotype, allele, autosomal dominant and recessive traits, and a monohybrid cross.

• What is a test cross and when is used? • Learn how to use the Punnett square to determine:

– genotypes and phenotypes and probability of offspring for autosomal dominant or recessive traits.

– the probability of passing of an X-linked gene and the phenotype to girls or boys based on the genotypes of the parents.

• Define X-linked genes and explain how the location of a gene on the X chromosome affect its gender-related transmission and pattern of inheritance.

• Review the factors affecting the phenotypes of Mendelian characters and provide examples for each: incomplete dominance, co-dominance & multiple allele, pleiotropy, polygenic inheritance, environmental effect, and epigenetics.

• Explain how gender is determined in mammals. • Explain X-inactivation and why is it present only in cells of females only and

genetic imprinting. • Explain the pattern of inheritance of genes present on the mitochondrial DNA.

Genetics (Plan) • Field of Heredity and Patterns of inheritance • Karyotype and terminology • Mendel, his contributions, and system he used • Mendelian pattern of inheritance of a single character and

applications (Student work sheets Q1 & Q2) • Mendelian Pattern of inheritance of 2 characters at the same

time • The laws of probability • Sex determination and pattern of inheritance of sex-linked

genes (Student work sheets Q1 & Q2) • X-inactivation • Factors influencing the phenotype of Mendelian characters

Patterns of Inheritance Gregor Mendel

- Studied variation in plants, patterns of

inheritance in garden peas - Used math to explain biological phenomena

These are sex chromosomes The chromosome pairs 1 trough 22 are autosome

Terminology Character or characteristic: a heritable

feature e.g. flower color

Trait: variant of the character e.g. purple or white

Mendel focused on characters with two variant phenotypes “either-or” traits

Mendel had control over which plants he crossed Colored Cotton Campbell video

http://www.dnaftb.org/

dnaftb/1/concept/

Mendel started with True-breeding plants F1 generation F2 generation F2 ratio

Purple flower- dominant trait

White flower- recessive trait

Mendel worked with pea plant characteristics with two traits each

Mendel was looking for a model that can account for the 3:1 ratio that he observed in the F2 generation

Mendel’s Model

1. An organism inherits two alleles (one from each parent).

2. One allele is dominant and the other is recessive

3. The two alleles segregate (separate) during gamete formation (Mendel’s law of segregation)

A Punnett square predicts the results of a genetic cross between individuals of known genotype.

Vocabulary used in Genetics An organism with two identical alleles is

homozygous for that character. Organisms with two different alleles for a character

is heterozygous for that character. A description of an organism’s traits is its

phenotype. A description of its genetic makeup is its

genotype.

Test Cross

Used to determine the genotype of a dominant trait

Pedigree Analysis

Mendelian characters of humans

• A pedigree can help us understand the past and to predict the future.

• We can use the normal Mendelian rules,

to predict the probability of specific phenotypes.

1. Pedigree analysis reveals Mendelian patterns in human inheritance

2. Many human disorders follow Mendelian patterns of inheritance

Examples of Genetic Disorders http://www.ygyh.org/ Tay-Sachs Sickle Cell Disease Cystic Fibrosis Huntington Disease

Segregation of characters • Monohybrid cross- inheritance of one

character • Dihybrid cross- inheritance of 2 characters Crossing true-breeding plant that have

yellow, round seeds (YYRR) with true-breeding plants that have green, wrinkled seeds (yyrr).

If the two pairs of alleles segregate independently of each other Gametes: P generation YR and yr F1 generation YR, Yr, yR, and yr These combinations produce four distinct phenotypes in a 9:3:3:1 ratio.

Probability Rules Applied to Monohybrid Crosses

The multiplication rule: The probability that two or more independent

events will occur together is the product of their individual probabilities

The rule of addition: The probability that any one of two or more

exclusive events will occur is calculated by adding together their individual probabilities

Mendelian inheritance reflects rule of probability

What is the probability of obtaining a

homozygote dominant? The probability of each independent allele is . The probability of two independent alleles occurring together Homozygote dominant X = Homozygote recessive X =

What is the probability of obtaining a heterozygote?

Under the rule of addition, the probability of

an event that can occur two or more different ways is the sum of the separate probabilities of those ways.

Heterozygote + =

X and Y Chromosomes X chromosome - Contains > 1,500 genes - Larger than the Y chromosome - Acts as a homolog to Y in males

Y chromosome - Contains 231 genes - Many repeated DNA segments

Figure 6.2

Anatomy of the Y Chromosome

Figure 6.3

Pseudoautosomal regions (PAR1 and PAR2)

- 5% of the chromosome - Contains genes shared with X

chromosome Male specific region (MSY) - 95% of the chromosome - Contains majority of genes

including SRY and AZF (needed for sperm production)

SRY Gene • Encodes a transcription factor protein • Controls the expression of other genes • Stimulates male development • Developing testes secrete anti-Mullerian

hormone and destroy female structures • Testosterone and dihydrotesterone (DHT)

hormones are secreted and stimulate male structures

Sex determination in Mammals: the X-Y system

Karyotype designation: 46, XY (male)

46, XX (female)

Germ cells in testes (XY) produce sperms with X: 50% Y: 50% Germ cells in ovaries (XX) produce only X eggs

• The sex chromosomes have genes for many

characters unrelated to sex • Each conception has about a fifty-fifty chance of

producing a particular sex

Y and X chromosomes are only partially homologous, they pair together during meiosis but rarely undergo crossing over

Synapsis of the X and Y chromosomes during prophase of meiosis I

http://www.hhmi.org/news/popups/page_ani.html

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SexChromosomes.html

Femaleness in mammals is the "default" program.

SRY gene (for sex-determining region Y)

- located on the short (p) arm

- the master switch that triggers the events that converts the embryo into a male

Evidence • Humans born with XXY, XXXY, and even XXXXY

abnormality, despite their extra X chromosomes, are males.

• XX humans have a translocation placing SRY on the X chromosome (male phenotype with testicular tissue)

• XY humans with a defective SRY are female • Transgenic female mice (XX) with an SRY gene are

phenotypically males with testis

The inheritance of genes of X chromosome follows special rules, because:

• males have only a single X chromosome • almost all the genes on the X have no

counterpart on the Y • any gene on the X, even if recessive in

females, will be expressed in males. • Genes are described as sex-linked or X-

linked.

X-linked Diseases Hemophilia A, a blood clotting disorder caused by

a mutant gene encoding the clotting factor VIII Duchenne muscular dystrophy http://www.ygyh.org Color blindness (X-linkage) http://www.biology.arizona.edu/human_bio/proble

m_sets/color_blindness/color_blindness.html

Human Chromosomes Homologous autosomes: 22 pairs = 44 chromosomes Sex chromosomes one pair XX or XY (X and Y share partial homology) Dose of expressed genes?

X-inactivation

In females, only one of the X chromosomes is active. The second is inactivated The inactive X chromosome appears as a condensed

chromosome during interphase (Barr body) http://users.rcn.com/jkimball.ma.ultranet/BiologyPage

s/S/SexChromosomes.html

X Y

X XX XY

Xh XhX XhY

Hemophilia A

In XhX heterozygote female, which X is active?

X-inactivation is random: 50% of cells Xh 50% of cells X

http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/SexChromosomes.html

X Inactivation A female that expresses the phenotype

corresponding to an X-linked gene is a manifesting heterozygote (calico cats)

Figure 6.12

The orange and black pattern on tortoiseshell cats is due to patches of cells expressing an orange allele while others expressing the non-orange allele.

Y-linked genes

The Y chromosome in males has 70 to 200 gene genes whose protein products are involved in:

a. control of changing sex of the fetus from female to male

b. development of male testes c. male fertility http://ghr.nlm.nih.gov/chromosome=Y

During fertilization sperm brings only the nuclear DNA, all mitochondrial DNA is maternal from the egg.

No Mendelian patterns of inheritance Can be used to determine maternal lineage

Chromosomal abnormalities caused by non-disjunction of • Homologous chromosomes during Meiosis I • Sister chromatids during Meiosis II

Factors Affecting Phenotypic Expression of Mendelian inherited characteristics

1. Incomplete dominance 2. Multiple alleles- co-dominance 3. Pleiotropy 4. Polygenic inheritance 5. Epistasis 6. Environmental effect 7. Epigenetic factors

Genotypic ratio same as phenotypic ratio

1. Incomplete dominance

Genotypes: HH

Homozygous for ability to make

LDL receptors

Hh Heterozygous

hh Homozygous

for inability to make LDL receptors

Phenotypes:

LDL LDL receptor

Cell

Normal Mild disease Severe disease

Incomplete dominance affects severity of disease

2. Multiple alleles, the human ABO blood system

ABO Blood grouping test

Multiple alleles of the ABO blood system - Three alleles, IA, IB, and I.

Both the IA and IB alleles are dominant to the i allele

The IA and IB alleles are co-dominant to each other.

- Because each individual carries two alleles,

there are six possible genotypes and four possible blood types.

3. Pleiotropy - A single gene may affect many phenotypic characteristics involving multiple systems - Sickle cell Disease http://www.ygyh.org/

Individual homozygous for sickle-cell allele

Abnormal hemoglobin crystallizes, causing red blood cells to become sickle-shaped

Sickle-cell (abnormal) hemoglobin

Sickle cells

Breakdown of red blood cells

Clumping of cells and clogging of

small blood vessels

Accumulation of sickled cells in spleen

Physical weakness

Anemia Heart failure

Pain and fever

Brain damage

Damage to other organs

Spleen damage

Impaired mental

function

Paralysis Pneumonia and other infections

Rheumatism Kidney failure

Quantitative characters show additive effect of multiple genes, e.g skin color and height in humans

4. Polygenic inheritance

Phenotype is determined by two separate genes, e.g coat color in mice B coat color gene C modifier gene

5. Epistasis

6. Environmental effects

Phenotype of Hydrangea flower color

• Blue flowers in highly acid soil • Pink flowers in neutral or slightly acid soil

7. Epigenetic factors Gene expression is impacted by chemical

modification of chromatin • DNA methylation • histone deacetylation

Prenatal Testing and Genetic Counseling Technological tools

• Sampling of fetal cells

a. Amniocentesis b. Chorionic Villus Sampling

• Biochemical tests • DNA testing- karyotyping and others

Chorionic Villus Sampling (CVS)

Genetic Testing & Personalized Medicine

(Learning Objectives)

1. Recognize the presence of common mutation within members of the human population (polymorphisms)

2. Recognize that information about such polymorphisms can be used for several purposes, such as: – Mutational analysis of disease causing genes – Genome –wide scanning for disease predisposition genes – Personalized Medicine

Single Nucleotide Polymorphism (SNP)

Variations in the DNA sequences of humans affect :

- Disease development - Response to: toxins, drugs, vaccines,

and chemotherapy.

Genome-wide screening • Genetic variation in human population • Correlation of certain base variability with

proximity to a disease causing gene • SNPs- single nucleotide polymorphisms

http://topics.nytimes.com/top/news/national/series/dnaage/i

ndex.html http://www.pathway.com/

Pros & Cons

Genetic Information Nondiscrimination Act GINA Bill