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)