Lecture 13: genetics Flashcards
Applications: crop breeding and animal husbandry
-traditional to:
>Improve yield
> Improve pest resistance
> widen geographical/ environmental range
>Make harvesting easier
-additionally, modern molecular techniques
>import characteristics from other species
Applications: Medical
-inherited diseases
>help identify disorder
>identify affected
individuals and carriers
> potential for gene-based
therapies
-multifactorial diseases
including cancer
>help identify risk factors
>help identify individual at
risk
>potential for gene-based
therapies
Applications: Forensic
-Genetic fingerprints
>identification of species
> identification of
individuals
-For the purpose of:
>paternity testing
>criminal investigations
>identification of disaster
victims
Chromosomes- structural types
> Metacentric- normal
Submetacentric- long arm
Acrocentric- short arm
Telocentric- missing the top half of the chromosome
Karyotype evolution
Karyotype evolution is where chromosome rearrangements contribute to evolution- over time it leads to a situation where chromosomes from different species cannot pair due to different chromosome numbers or different regions being on different chromosomes
Chromosome fusion and fission
> Changes in chromosome number can derive from chromosome fusion or fission
In chromosome fusion (a), two telomeres and one centromere lose function
In chromosome splitting (b), a new centromere must develop and telomeres must be added at the new ends
-e.g. some sequence blocks from a single chromosome in pigs, cows and horses are on two chromosomes in humans
Ideogram
> Each gene has specific location, in specific chromosome and cytoband
Xp11.21,for example, has gene KLF8. Expresses only in heart
Duplicated genes
> Duplicated genes can develop different functions over time, resulting in gene and protein families
α and β-globin gene families are derived from a single ancestral globin gene
Humans have 3 protein-coding genes at the α-locus and 5 at the β-locus, plus pseudogenes that have lost function
The coding genes have specialized functions and times of expression
Functional divergence
> Functional divergence can occur when different family members are expressed in different tissues
The hedgehog family encodes signalling molecules, important for development, that are expressed in different tissues
Sonic, desert and Indian are paralogs (related copies of a gene in a single species)
Orthologs are genes in different species that are derived from a common ancestor (sonic, desert and Indian are orthologs of Drosophila hedgehog)
Homologs are inferred from sequence similarity and are descended from a common ancestor
When genes are duplicated, evolutionary pressure is reduced as there is a spare gene copy – this is why functional divergence can occur
Mutations can thus reduce or eliminate function in some copies without detriment to the organisms – pseudogenes (non-functional gene remnants)
Genes in a gene family with highly similar sequences can be present - Recent duplication - Strong selection to maintain selection - Gene conversion (repair using another copy as template, which homogenizes the sequences)
Ploidy
> Refers to the number of sets of chromosomes in a cell
-one set= n chromosomes
-n monoploid
-2n diploid (gametes n-
haploid)
»_space;in humans n=23
-3n triploid, 4n tetraploid…
»_space;incompatible with life
In humans
-Extra or missing chromosomes from a set. E.g. 2n+1, 2n-1 are aneuploid (an=not, e.g. eu=true, +ploidy, I.e not composed of full sets)
Monohybrid Cross (Punnett square)
> Used to determine phenotype and genotype of offspring (F1 generation)
Phenotype= physical (colour, shape, appearance)
Genotype= gene or allele (Aa, AA, aa)
Dominant= trait always displayed (AA,Aa)
Recessive= trait always masked; only expressed when homozygous (aa)
Homozygous Dominant- AA
Heterozygous- Aa
Homozygous recessive- Aa
Co-dominance
> All traits are dominant (no recessive; lowercase alleles)
In co-dominance, both traits are expressed
Red fish (R) X Blue fish (B)= Red/Blue fish
ABO blood groups
> There are 4 possible blood groups: A, B, O, AB
If you are AB, neither of your parents are O
If you are O neither of your parents are AB
There are few exceptions to this rule
One locus, 3 alleles IA, IB, i
IAIA or IAi –> group A
IBIB or IBi –> group B
ii –> group O
IAIB –> group AB
alleles are CODOMINANT
The alleles IA and IB code for enzymes which attach sugar residues to red blood cell surfaces
Incomplete dominance
> All traits are DOMINANT (no recessive; lower cased alleles)
In incomplete dominance, traits blend together.
Ex. Red flowers (R) x White flowers (W) = Pink Flowers
Sex-linked traits- ‘X-linked traits’
> Affects the sex chromosomes (pair #23)
Most Sex Linked Traits affect the X chromosome.
Males are more affected by sex-linked traits because they only have one X chromosome
Females are often carriers because they have two X chromosomes
Meiosis
> Makes Gametes (sex cells)
Divides adult chromosome number in half (haploid); so that parents only pass 23 chromosomes to offspring.
Meiosis I: Homologous chromosomes
a) Crossing Over (swapping of chromosomes from mom & dad). Occurs in Prophase I
b) Law of Independent Assortment: states that alleles (genes) that you receive from your parents sort RANDOMLY; during Meiosis when your gametes are being made. The reason why you are genetically different, and look different from parents.
c) Non Disjunction (chromosomes do not separate properly), adding one chromosome, causing Down Syndrome, Klinefelter’s, Turner Syndrome
Meiosis II: Sister Chromatids
End result; four daughter cells with 23 chromosomes. Meiosis II and Mitosis are similar
Events in meiosis
> Crossing Over: Occurs in Prophase I, where the chromosomes break, and exchange genetic material
Why organisms look different than parents
Non-disjunction: failure of chromosomes to separate properly, causing organism to have extra chromosome (Trisomy 21)
Karyotypes and genetic disorders
> Karyotypes are mapping of human chromosomes
A normal human karyotype has 46 chromosomes (diploid), and 23 pair (haploid).
Chromosomes 1-22 are called autosomes.
The sex chromosomes are the 23rd pair
Males are XY; females are XX
Sex determination
> All diploid human cells have 22 pairs of AUTOSOMES (44A)
Females have 2 copies of the X chromosome (44A XX)
Males have one X and one Y chromosome (44A XY)
Note that X and Y are not strictly a pair of chromosomes as they don’t carry the same genes
All children inherit an X from their mum and either X or Y from their dad
Human aneuploids
> Single sex chromosome- XO= Turner syndrome
Extra set chromosomes
-XXX
-XXXX
-XXY Klinefelter
-XYY
Trisomy 21= Down syndrome
Trisomy 18= Edwards syndrome
-Trisomy 13= Patau’s syndrome
Cystic fibrosis
> Thick mucus in the lungs and digestive tract
Mainly affects Caucasian population
1 in 28 Americans carries the trait
Caused by defective protein cell membrane
Treated with special diet, and physical therapy
Tay-sacs disease
> Caused by recessive trait
An important enzyme (protein) is missing that breaks down lipids (fat) in the central nervous system.
Fat (lipids) accumulates in the CNS causing damage
Sickle cell anemia
> Primarily affects the African-American Community
Red blood cells are crescent shaped
Pain in the extremities
Caused by Point (substitution) mutation
Patients with SCA are immune to Malaria
Glucose-6-phosphate dehydrogenase deficiency
> Occurs almost exclusively in males
Mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body
A defect in Glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely
The most common medical problem associated with G6PD deficiency is hemolytic anemia, which occurs when red blood cells are destroyed faster than the body can replace them
An estimated 400 million people worldwide have G6PD deficiency.
Most frequent in certain parts of Africa, Asia, the Mediterranean, and the Middle East. It affects about 1 in 10 African American males in the United States
G6PD deficiency is also a significant cause of mild to severe jaundice in newborns
Many people with this disorder, however, never experience any signs or symptoms and are unaware that they have the condition
G6PD mutations
> Glucose-6-phosphate dehydrogenase deficiency results from mutations in the G6PD gene
Protein function is linked to carbohydrate processing
It also protects red blood cells from the effects of potentially harmful molecules, i.e. reactive oxygen species (ROS)
Chemical reactions involving glucose-6- phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells
Problems with G6PD deficiency
> If mutations in the G6PD gene reduce the amount of glucose-6- phosphate dehydrogenase or alter its structure, this enzyme can no longer play its protective role
As a result, reactive oxygen species can accumulate and damage red blood cells
Factors such as infections, certain drugs, or ingesting fava beans can increase the levels of reactive oxygen species, causing red blood cells to be destroyed faster than the body can replace them
A reduction in the number of red blood cells causes the signs and symptoms of hemolytic anemia
Malaria and G6PD
> People with G6PD mutation may be partially protected against malaria, an infectious disease carried by a certain type of mosquito
A reduction in the amount of functional glucose-6- phosphate dehydrogenase appears to make it more difficult for this parasite to invade red blood cells
Glucose-6-phosphate dehydrogenase deficiency occurs most frequently in areas of the world where malaria is common
Inheritance
> This condition is inherited in an X-linked recessive pattern
The gene associated with this condition is located on the X chromosome
In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition
In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder
Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females
A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons
DNA analysis for phenotypic characteristics
> No single gene or variation determines our eye colour
12-13 specific single nucleotide changes.
Linked to our hair and skin colour as well
PKU (Phenylketonuria)
> Recessive disorder
Missing an enzyme that converts the amino acid Phenylalanine into Tyrosine.
Phenylalanine cannot be broken down by the body and causes damage to the CNS
Patients treated with diet low in phenylalanine
Phenylalanine is found in many diet sodas.
Disorder of phenylalanine metabolism
parents of PKU children are usually symptom free
the family may have both affected and unaffected children
Alleles
> The location of a gene is called the LOCUS (plural: loci)
For autosomes, and X in female, there are two copies of each gene, one on each chromosome
If we have the same allele on each chromosome, we are HOMOZYGOUS for that gene
If we have different alleles on each chromosome, we are HETEROZYGOUS for that gene
The male is HEMIZYGOUS for genes on the X chromosome, as he has only one copy of each
Genetic dominance
> In the heterozygote, one allele may be expressed in the phenotype and the other not expressed.
The expressed allele is said to be DOMINANT and the non-expressed allele is RECESSIVE. These terms only refer to a specified pair of alleles.
PKU
> Allele A is active
Allele a is inactive
You have two alleles, one inherited from each parent
AA and Aa can both make PAH – healthy phenotype
aa cannot make PAH – has PKU
Monohybrid cross
> Both parents heterozygous for the characteristic in question
Genotypic ratio: 1AA : 2Aa : 1aa
Phenotypic ratio: 3A : 1a
Can calculate probability of a particular phenotype or genotype but CANNOT predict an individual genotype or phenotype
Simplest MENDELIAN RATIO
Polymorphic loci
> Each individual has two copies of the gene and therefore two alleles
There may be lots of alleles in the population as a whole e.g>300 alleles for haemoglobin. Estimates suggest that 1 person in 20 has a variant from the most common allele of Hb.
Most variation is PHENOTYPICALLY SILENT but may affect our risk of diseases such as cancer and heart disease
This variation is individual and the basis of forensic genetic tests
Huntington’s disease
> Degeneration of Nerve Cells (neurons)
Cognitive impairment
Inability to focus
Muscle rigidity
No treatment
When symptoms arise, death in 10-25 years
Neuron Apoptosis –> (neurons die)
Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition)
Huntington disease affects an estimated 3 to 7 per 100,000 people of European ancestry.
The disorder appears to be less common in some other populations, including people of Japanese, Chinese, and African descent
HTT gene
> Caused by mutations in HTT gene
Protein is called huntingtin
Probably linked to neuron functionality
Disorder of trinucleotide repeat CAG
Normally repeated 10 to 35 times
By definition, Huntington patients have a stretch of 36 to >over 120 repeats
CAG-CAG-CAG-CAG-CAG…
Clinical symptoms of Huntington disease
> An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein
The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells
The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease
Inheritance of Huntington’s disease
> This condition is inherited in an autosomal dominant pattern
-which means one copy of the altered gene in each cell is sufficient to cause the disorder
An affected person usually inherits the altered gene from one affected parent
In rare cases, an individual with Huntington disease does not have a parent with the disorder
As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size
HD
> The mutant allele is dominant to the nonmutant allele in the heterozygote, so only one copy of the mutation is required for disease manifestation
HH (homozygote) and Hh (heterozygote) seem to be equally affected (not always true for dominant diseases)
Mutation type is called a trinucleotide repeat, which tends to get worse in every generation
Xeroderma pigmentosum (XP)
> Rare disorder; it is estimated to affect about 1 in 1 million people in the United States and Europe
The condition is more common in Japan, North Africa, and the Middle East
Autosomal recessive genetic disorder of DNA repair in which the ability to repair damage caused by ultraviolet (UV) light is deficient
Patients are extreme sensitivity to ultraviolet (UV) rays from sunlight
Symptoms arise usually in early childhood
XP characteristics
> Increased risk for skin cancer
The eyes of people with xeroderma pigmentosum may be painfully sensitive to UV rays from the sun
Without sun protection, about half of children with this condition develop their first skin cancer by age 10
Most people with xeroderma pigmentosum develop multiple skin cancers during their lifetime.
These cancers occur most often on the face, lips, and eyelids
Genetics of XP
> Many of the genes related to xeroderma pigmentosum are part of a DNA-repair process known as nucleotide excision repair (NER)
The major features of xeroderma pigmentosum result from a buildup of unrepaired DNA damage
Inherited mutations in at least eight genes have been found to cause xeroderma pigmentosum.
More than half of all cases in the United States result from mutations in the XPC, ERCC2, or POLHgenes.
Mutations in the other genes generally account for a smaller percentage of cases.
Rodent carcinogen tests
> Rats and mice exposed to high dose of a test compound for an extended period of time
Histopathological examination for tumours that may have arisen in the exposed rat/mice
Aflatoxin B
> Unlike most fungi, Aspergillus flavus is favored by hot dry conditions
Aspergillus flavus can also be pathogenic on several plant and animal species, including humans and domestic animals
Induces G to T transversions, thought to be involved in hepatocellular carcinoma
Codon 249 in p53 tumoursuppressor gene
Somatic mutations
occur in any cell except germ cells and are not heritable
Germ-line mutations
occur in gametes and are inherited
Autosomal mutations
occur within genes located on the autosomes, whereas X-linked mutations occur within genes located on the X chromosome
Consanguinity
> Occurs when parents are closely related e.g. brother/sister, parent/child, aunt/nephew, uncle/niece, first cousins
Raise the chances that both parents are heterozygous for a mutation, so recessive alleles are more likely to be expressed
Compound heterozygote
> The two alleles have different mutations within the same gene
Albinism
> An inability to make the pigment which colours skin, hair etc
Two normally pigmented individuals may have albino children
A normally pigmented individual and an albino may have an albino child
Two unrelated albinos may have normally pigmented children
What is phenotype?
> Phenotype is ‘outward appearance’ – it doesn’t always tell us about the genotype
Melanin is the end product of a metabolic pathway; mutations affecting any of several different enzymes can result in a failure to make pigment
DIFFERENT GENOTYPES
SAME PHENOTYPE
Suppose two loci are involved
> X –> Y –> Z
Locus 1: alleles A and a
-enzyme catalyses XY
Locus 2: alleles P and p
-enzyme catalyses YZ
What genotypes would give normal pigmentation?
What genotypes would give albino pigmentation?
Use of Punnett squares
> Work from parental gametes to ensure you have all possible genotypes and phenotypes of offspring
If both parents are heterozygous at each locus, AaPp, you should get 16 possible combinations of gametes and a phenotypic ratio in children of 9AP:3Ap:3aP:1ap. If you need both A and P for normal pigmentation, you have 9/16 chances of getting this combination.
This is the second MENDELIAN RATIO, the dihybrid cross
