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
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