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 autosomaldominant 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 the system he used• Mendelian pattern of inheritance of a single character and

applications (Student work sheets)• 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)• X-inactivation• Factors influencing the phenotype of Mendelian characters

Patterns of InheritanceGregor Mendel

- Studied variation in plants, patterns of inheritance in garden peas

- Used math to explain biological phenomena

These are sex chromosomesThe chromosome pairs 1 trough 22 are autosome

TerminologyCharacter 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 generationF2 generationF2 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 Model1. 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 squarepredicts the results of a genetic cross between individuals of known genotype.

Vocabulary used in GeneticsAn 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 Mendelianpatterns in human inheritance

2. Many human disorders follow Mendelianpatterns of inheritance

Examples of Genetic Disordershttp://www.ygyh.org/

Tay-SachsSickle Cell DiseaseCystic FibrosisHuntington Disease

Segregation of characters

• Monohybrid cross- inheritance of one character

• Dihybrid cross- inheritance of 2 charactersCrossing 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 yrF1 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 togetherHomozygote 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 ChromosomesX 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 withX: 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

http://www.nature.com/ejhg/journal/v16/n7/fig_tab/ejhg200863f1.html#figure-title

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 DiseasesHemophilia A, a blood clotting disorder caused by

a mutant gene encoding the clotting factor VIII

Duchenne muscular dystrophyhttp://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 chromosomesSex 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/BiologyPages/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

Figure 6.12

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

X InactivationA 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 testesc. 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-dominance3. Pleiotropy4. Polygenic inheritance5. Epistasis6. Environmental effect7. Epigenetic factors

Genotypic ratio same as phenotypic ratio

1. Incomplete dominance

Genotypes:HH

Homozygousfor ability to make

LDL receptors

HhHeterozygous

hhHomozygous

for inability to makeLDL receptors

Phenotypes:

LDLLDLreceptor

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 homozygousfor sickle-cell allele

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

Sickle-cell (abnormal) hemoglobin

Sickle cells

Breakdown ofred blood cells

Clumping of cellsand clogging of

small blood vessels

Accumulation ofsickled cells in spleen

Physicalweakness

Anemia Heartfailure

Pain andfever

Braindamage

Damage toother organs

Spleendamage

Impairedmental

functionParalysis Pneumonia

and otherinfections

Rheumatism Kidneyfailure

4. Polygenic inheritance

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 geneC 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 long non-coding RNAs and marked with chemical modification of chromatin

• DNA methylation• histone deacetylation

Prenatal Testing and Genetic Counseling

Technological tools

• Sampling of fetal cellsa. Amniocentesisb. Chorionic Villus Sampling

• Biochemical tests• DNA testing- karyotyping and others

Chorionic Villus Sampling (CVS)