Mutations and germ pools

What is evolution

·      Evolution describes the change in the characteristics of a species over time

·      It is a theory that explains the mechanisms that drive species to change over time

·      Change is gradual, occurs over many generations (thousands and millions of years)

What is genes, alleles, genotypes, phenotypes

•       Gene: A segment of DNA made up of a sequence of nucleotides that code afor the production of a specific protein

•       Alleles: The variations of a particular gene that can be inherited

•       Genotypes:  The combination of alleles inherited from parents (mother & father) for a particular gene

•       Phenotypes: The observable characteristic that is the result of a genotype

Mutations

·      A new variation, resembling neither parent, that occurs quite suddenly and purely by chance.

·      Permanent structural alterations in the DNA.

·      Occur through changes to genes or chromosomes.

·      In some cases, changes to the DNA have little effect or cause no harm.

·      Occasionally a mutation can improve an organism’s chance of surviving.

·      Mutant – an organism with a characteristic resulting from a mutation.

Mutations can be classified as either:

1. Gene mutations – changes in a single gene.

2. Chromosomal mutations - all or part of a chromosome is affected.

extra info

·      If a mistake occurs spontaneously when the DNA molecule is copied during cell division, or when chromosomes are separated during meiosis  creates significant effects on the functioning of the cell.

·      Many mutations are repaired by the body.

·      If a mutation remains, when the cell divides, the mutated DNA is copied and passed onto daughter cells.

·      If daughter cells are gametes – mutation will be passed on from one generation to the next.

·      Relatively few mutations exists amongst humans given the extremely large number of cell divisions that occur.

o   Usually if a mutation occurs, it results in a trait that is better suited to the environment and contributes to a greater chance of survival

Mutagens/Mutagenic Agents

•       Any agent that increases the rate at which mutations occur.

•       Examples include X-rays, mustard gas, UV radiation, cosmic rays, radiation from radioactive waste, fallout from atomic and nuclear explosions.

Mutagens also affect developing embryos/foetuses:

•       If pregnant women are exposed to mutagens (eg: large doses of X-rays), then their child may be born with intellectual disabilities

Causes of Mutations

•       Induced mutations: Mutations caused by mutagens in the environment.

•       Spontaneous mutations: Mutations that occur due to a random error during cell division (mitosis or meiosis)

Heritability of mutations

Somatic mutations – mutations that occur in body/somatic cells.

•          ONLY the individual with the somatic mutation is affected.

•        Involved in many cancerous growths resulting from a mutagenic agent.

Germline mutations – mutations that occur in the reproductive cells/gametes.

•        individual is not usually affected.

•       may be passed on to the next generation and subsequent generations.

Effects of Mutations

1. Silent mutations: does not cause a change in the amino acid produced by the mutated codon

Eg: GAG (Glu)  GAA (Glu)

2.        Neutral mutations: causes a change in the amino acid produced by the mutated codon, but the structure of the protein produced does not change enough for its function to change

Eg: GAG (Glu)  GAC (Asp)

3.        Missense mutations: causes a change in the amino acid produced and therefore the protein

Eg: GAG (Glu)  AAG (Lys)

4.        Nonsense mutations: changes the codon to STOP, producing a shorter protein

Eg: GAG (Glu)  UAG (STOP)

Point mutation

A change in just one base is known as a point mutation  (SNV)

Point mutations can form:

1. Substitution of a base for another base.

2. Insertion of a base.

3. Deletion of a base.

Frame Shift Mutations – Insertion/ Deletion

•       Inserting or deleting one or more nucleotides changes the “reading frame” of the DNA sequence (similar to changing how a sentence is read).

•       Alters how the codons are read during protein synthesis and therefore results in proteins being built incorrectly – has huge impact on organisms

cont

Effect of Point Mutations (SNV

•       No effect on protein, abnormal protein – may be non-functional or missing protein.

•       Proteins include enzymes, antibodies, structural proteins, membrane transport channels etc.

•       Just one missing or abnormal protein can have an enormous effect on the entire body.

Albinism

·      Albinism, is the result of one missing protein, tyrosinase. (enzyme involved in melanin production)

·      Partial or complete absence of pigment from the hair, skin, and eyes.

·      Prone to skin cancers.

Duchenne Muscular Dystrophy

-       Affects boys due to germline mutation in the mother, which can then be inherited by her sons.

-       May also occur in a male zygote so that the child develops the disease.

-       It’s a wasting of the leg muscles and later the arms, shoulders and chest

-       Apparent around the age of 3 to 5 years, when muscle weakness becomes evident.

-       Young boys may stumble easily and have difficulty in climbing and frequently have to push their hands down on their legs to stand.

-       As a boy gets older muscle tissue is replaced by fat.

-       By around 12 to 14 years of age the child is unable to walk and later becomes bed-ridden.

-       Death occurs due to failure of the respiratory muscles.

-       Boys with the Duchenne form of muscular dystrophy are unlikely to live for more than 20 to 25 years.

Cystic fibrosis

-       Occurs in a huge gene (CFTR) which is found on Chromosome 7

-       It is inherited as autosomal recessive.

-       Over 500 different recessive mutations of the CFTR gene have been identified including deletions, missense, nonsense, terminator codon.

-       The gene has the code for 1480 amino acids that make up a protein that regulates the passage of chloride ions across the cell membrane.

-       Secretions dry because water usually follows chloride by osmosis.

-       Common in Caucasians (1 in 26 carriers) – more resistant to cholera check.

Cystic Fibrosis – Treatment

-       Drainage of lungs – lie on side to move secretions to other side.

-       Chest physiotherapy - up to a few times a day.

-       Deep breathing exercises.

-       Nebuliser mask – saline mist to moisten secretions.

-       Lung transplant can help.

-       A modified diet – high fat diet.

-       Supplementary pancreatic enzymes

-       The use of antibiotics including (Tobramycin solution for Inhalation) to control lung infections.

Future:

Gene therapy inserting normal CFTR gene using adenoviral vectors and liposomes.

What is chromosomal mutation

·      Involves all or part of a chromosome being mutated

·      Consequently, a number of gene are affected

·      Occurs due to errors during cell division especially in egg and sperm cells, therefore offspring are affected by mutation.

Types of chromosomal mutations

o   Deletions

o   Duplications

o   inversions

o   Translocations

o   Non-disjunctions

Deletion

•       Due to breakage; a piece of a chromosome is lost.

Inversion

•       Chromosome segment breaks off; segment flips around backwards; segment reattaches.

Duplication

•       Occurs when a gene sequence is repeated.

Translocation

•       Involves two chromosomes that aren’t homologous.

•       Part of one chromosome is transferred to another chromosomes.

Non-disjunction

•       Failure of chromosomes to separate during meiosis.

Causes gametes to have too many or too few chromosomes.

Effects of deletions, inversions, duplication and translocations depend on their locus (genes involved).

Deletions – gametes missing genes are often inviable (can’t survive) or result in miscarriage early in the pregnancy. Known to cause Wolf-Hirschhorn syndrome, Jacobsen syndrome, 

Inversions – all genes are still present therefore offspring is unaffected, however, unusual order causes difficulties in crossing over during meiosis  infertility.

 

Duplication – extra DNA can cause symptoms. Known conditions include  Charcot-Marie-Tooth disease type 1A

Translocation – All DNA is still present so the organism has no symptoms, however, gametes will receive chromosomes with extra or missing DNA  infertile.

terminology

Aneuploidy= a change in the chromosome number.

Disomy = 2 copies of each chromosome. Normal for human somatic cells.

Trisomy = 3 copies of a chromosome.

Monosomy = 1 copy of a chromosome.

•       One extra (trisomy) or one missing (monosomy) chromosome has major consequences as there are many extra genes and therefore extra proteins being produced  usually fatal  miscarriage.

Aneuploidy

Aneuploidy may involve autosomes:

 - Patau syndrome:                     Chromosome 13

 - Edward syndrome:                  Chromosome 18

 - Down syndrome:    Chromosome 21

Aneuploidy may involve sex chromosomes:

  - Klinefelter syndrome:      XXY

  - Turner syndrome:    XO

Why are they called syndromes?

•        When a disease causes multiple effects, it is called a syndrome.

•        Virtually all chromosome abnormalities are in this category.

Partial Monosomy 5 – Cri du Chat

•       From the French for ‘cry of the cat’,

•       A rare genetic disorder due to a missing portion of chromosome 5.

•       The infant sounds just like a meowing kitten, due to problems with the larynx and nervous system. About one third of children lose the cry by age 2.

•       Other symptoms may include feeding problems because of difficulty swallowing and sucking, low birth weight and poor growth, and unusual facial features which may change over time.

•       Varying levels of mental handicaps.

·      Edward Syndrome - Trisomy 18

o   The next most common trisomy after Down syndrome but much more severe.

o   Incidence rate of 1 in 6 000 live births (with a
weak maternal age effect).

o   Females are affected more than males (ratio of 1:2 of males: females.

o   Commonly a result of non-disjunction in meiosis I or II or, more rarely translocation.

o   Mosaicism also occurs where mutation occurs in infant  only some cells affected.

Down Syndrome - Trisomy 21

•       This is the most common form of aneuploidy in human newborns that remain viable at birth.

•       Incidence rate of 1 in 800 births in women giving birth at 30 to 31 years of age. Relatively frequent in children of older mothers.

Causes

•       There are three causes of Down syndrome, each producing a different severity of the syndrome.

•       95% of all cases result from non-disjunction of chromosome 21 during meiosis (see the karyotype right).

•       3-4% result from translocation of chromosome 21 (usually on to chromosome 14).

•       1-2% arise from a failure during mitosis  (non-disjunction of chromosome 21) in a cell of a very early embryo. The resulting individual is a ‘mosaic’ of normal and Down syndrome cells.

Sex chromosome disorders

Lethal Recessive mutation

·      Some recessive mutations are lethal if they are not masked by a dominant normal allele.

·      These lethal recessives cause the death of the embryo or foetus (a miscarriage or spontaneous abortion) or the early death of the child.

·      Lethal recessives – inheritance of two recessive alleles for particular mutations/disorders

·      eg: Tay-sachs; Cystic fibrosis; sickle-cell anaemia; achnondroplasia – bone disorder causing disproportionate dwarfism; short limbs, normal sized torso – one from each parent – is fatal (causes death)

·      If only one of the lethal recessives allele is inherited – usually not fatal

Tay-Sachs Disease (TSD)

·      Tay-Sachs disease (TSD) is a disorder of lipid metabolism that is inherited in an autosomal recessive pattern.

·      It occurs most frequently in individuals of Jewish descent from eastern Europe (the Ashkenazi Jewish population).

·      This is a lethal recessive condition as the missing enzyme results in the accumulation of a fatty substance in the nervous system.

·      A baby with two recessive alleles for TSD develops normally for the first few months, and then deterioration causing mental and physical disabilities begins.

·      Death usually occurs in early childhood.

population, gene pool, gene frequency definition

•       Population: A group of organisms of the same species that live in the same place at the same time and are reproductively isolated and breed with each other (i.e. humans can only breed with humans)

•       Gene pool: Total sum (amount) of alleles within a population

•       Allele frequency: How often an allele of a gene is present within a gene pool.

Allele frequency

·      Frequency of a particular allele can differ between populations

·      Eg 1: Scandinavians commonly have blue eyes, whereas Sub-Saharan Africans commonly have brown eyes.

o   Frequency of blue eye allele in Scandinavian population is greater than in Sub-Saharan African population

·      Allele frequencies also differ over time and are not usually constant

·      Eg 2: Frequency of lighter skin colour in Australia

o   In 1700, the frequency of lighter skin individuals was 0%

o   In 2016, the frequency of light skin individuals was approx. 89%

cont

·      Over time, the frequency of alleles changes and can be affected by:

§  Mutation of an allele

§  Migration & gene flow

·      When an individual of same species migrates from one population to another population in a different area, - gene flow is occurring.

o   Immigration of individuals - Movement into a population – May add new alleles

o   Emigration of individuals - Movement out of a population – May completely remove some alleles

o   Reproduction rate of various individuals - Number of offspring born that year