Genetic Variation

Genetic Inheritance & VariationNo 2 organisms in a sexually reproducing species are the same (except clones or monozygotic twins)Genetic variation is essential for evolution and change to occurThere are 2 main processes that generate variation:MutationRecombination

Mutation and RecombinationMutation is a change in the genetic informationRecombination is a different arrangement of the same genetic materialThe cat sat on the mat (1)The bat sat on the hat mutation (2)The cat sat on the hat recombination of 1 and 2

The main properties of DNAThe genetic material must be able to:Store informationReplicate (when cells divide)Express information (as proteins)Mutate at a low frequency (less than 1 in a million)DNA is a molecule that is very well suited to doing all 4 of these

MutationCan occur in any cell at any time, cause may be:Internal (e.g. mistakes during replication of DNA)External (e.g. radiation, chemicals)Most mutations have no effect (neutral)A few mutations are harmful A very few mutations are beneficialOnly harmful and beneficial mutations are acted on by natural selectionMutations may be non-coding (not in part of gene that codes for protein - have no effect, or affect gene expression) or coding.

Effects of coding mutationsSynonymous: the cat ate the ratMissense:the fat ate the ratNonsense:the cat ate theFrameshift:the cax tat eth era tSynonymous has no effect on protein, nonsense makes a smaller protein, missense/frameshift make incorrect protein

Conditional mutationsThe effects of many coding mutations depend on environmental factorsSiamese cats have mutation in enzyme for black pigment production, that stops it working at normal body temperatureCooler parts of cat are dark because enzyme OK at lower temperature

Mutation during DNA replicationReplication of DNA is not perfectly accurate, but there are several ways to correct the mistakesACGTACGTAACGTG...TGCATGCATTGAACGGTDNA polymerase makes about 1 mistake per 105 bp.DNA polymerase has a proof-reading activity to correct itsown mistakes (99%).After DNA replication there is a mismatch repair system tocorrect remaining mistakes (99.9%).This leaves an overall error rate of about 1 base in 1010.

Error correction in DNA replicationOverall error rate is about 10-10 per divisionAbout 1 mistake per cell per division in humans

Mutation due to environmental factorsMutations may be caused by chemicals or radiationChemicals (mutagens) may disrupt hydrogen bonds between bases, by modifying them or getting between themRadiation (including ultra-violet and radioactive emissions) can damage structure of basesThese agents may be natural or man-made

DNA excision repairAnother system to repair mutated or damaged DNAMutated DNAOne strand is nickedDNA removed between nicksCorrect DNA is synthesised

Mendels experimentsGregor Mendel (a 19th century Czech monk) worked out the basic laws of genetic inheritance by breeding pea plantsHe chose simple characteristics that are determined by single genes (monogenic)Many characters such as height, IQ, disease susceptibility are determined by several genes (polygenic)

Mendels first crossP1 (parental) generation: wrinkled seedscrossed with smooth seedsF1 generation: all smooth seeds. Crossedwith itself...F2 generation: smooth and wrinkled in ratio 3:1

Mendels genetic hypothesisAAaaAaGenes come in pairs. Each of the parents has2 copies of this gene. The A form gives smoothseeds, the a form gives wrinkled.Parents produce gametes (eggs, sperm, pollen)which have 1 copy of the gene.Fertilisation produces the F1 generation, all smooth because the A form is dominant over a;a is recessiveEach F1 plant produces equal numbers of A and a gametes which fertilise at random to produce the F2plants. 1/4 of them are AA (smooth), 1/2 are Aa(smooth) and 1/4 are aa (wrinkled).

Cross with two genesABabAABBaabbAaBbABabaBAb4 types of gametesin equal numbers9/16 yellow/smooth3/16 green/smooth3/16 yellow/wrinkled1/16 green/wrinkled

Summary of Mendels experimentsGenes in an organism come in pairsSome forms (alleles) of a gene are dominant over other alleles which are recessiveOne (at random) of each pair of genes goes into a gamete (segregation)Gametes meet randomly and fertiliseThe numbers and types of offspring in a cross are determined by the above lawsSeparate genes behave independently of each other (later, exceptions to this rule were found)

Genes and chromosomesGenes can have several different forms due to mutations in DNA sequence. These forms are called alleles. Property of having different forms is called polymorphismNormal human body cells (somatic cells) are diploid: 23 pairs of chromosomes: Numbers 1-22 (autosomes) X and Y (sex chromosomes)XX in females, XY in malesGametes (eggs, sperm, pollen) are haploid, i.e. they have a single copy of each chromosome

Phenotype, Genotype, AllelesThe phenotype of an organism is its observable propertiesThe genotype is the set of alleles it has for all of its genes (5,000 in bacteria; 35,000 in humans)New alleles are created by mutation and their effect the phenotype may be dominant or recessive

Significance of genetic variationSome alleles directly cause specific traits, such as (in humans) rare genetic diseases e.g. Cystic fibrosis, sickle-cell anaemia; (in bacteria) ability to grow on certain sugarsMany alleles contribute to many traits of an organism such as size, shape, intelligence, behaviour, and risk of getting diseases e.g. (in humans) cancer, heart disease, asthma Genetic variation is what evolution acts on. Without it there would be no different species.

Multiple genes and quantitative traitsMany traits like height, IQ show a bell-shaped (normal) distribution in populationThese are influenced by several genes, so the overall effect depends on the random selection of alleles in an individuale.g. for height genes, you are more likely to have a mixture of tall and short alleles than all tall or all shortheightnumber

Genetic Linkage and RecombinationMendel was lucky - the genes he chose all segregated independentlyThis is not true of all genes - many genes are linkedIn humans, there are 23 pairs of chromosomes and about 35000 pairs of genes - each chromosome has a few hundred to a few thousand genesGenes close together on the same chromosome are linked and do not segregate independently

Terms & DefinitionsGenes can have several different forms due to mutations in the DNA. These forms are called alleles. Property of having different forms is called polymorphismOrganism with 2 copies of the same allele of a gene in diploid cells is homozygous for the geneOrganism with different alleles of a gene in diploid cells is heterozygous for the geneMales are hemizygous for genes on X and Y chromosomes

Modes of inheritanceDominant alleles affect the phenotype when present in 1 copy (heterozygous), e.g. Huntingtons diseaseRecessive alleles affect the phenotype only when present in 2 copies (homozygous), e.g. cystic fibrosisCan tell whether dominant or recessive by studying Mode of Inheritance in families

Autosomal dominant inheritancePerson with trait in each generationMales and females equally likely to show trait Where 1 parent is heterozygous,about 50% of offspring show traitExample: Huntingtons disease

Autosomal recessive inheritanceTrait may skip generationsMales and females equally likely to show traitHeterozygotes (carriers) do not show traitAbout 25% of offspring of 2 carriers will show traitExample: cystic fibrosis

X-linked recessive inheritanceCarrier (heterozygous, unaffected) mothers pass the traitto about 50% of sonsTrait is never transmittedfrom father to sonIn the population, trait will be much more common in malesthan females. Example: muscular dystrophy

Jumping genesGenomes are not always stable. Some DNA sequences can jump from one place to another (transposons) Transposons can be responsible for things like antibiotic resistance in bacteria They can also affect the expression of a gene near to where they jumpIf a transposon jumps in some cells but not others, can get a variegated phenotypeMaize (corn) cob

Transposon mechanism

Oogenesis & spermatogenesis (animals)Oogenesis is the process of egg formationSpermatogenesis is the process of sperm formationBoth go through several stages, with (in mammals) different timing in males than femalesSperms go through more cell divisions than eggs do - more chance of mutation

Fertilisation2 haploid cells (egg, sperm) form 1 diploid cell (the zygote) which develops into the embryoWhether sperm contained an X or Y chromosome determines if embryo is female or maleEmbryo contains an assortment of genes from each original parent - more genetic diversityMitochondria (and their DNA) come only from mother via the egg - maternal inheritance

MeiosisProcess of cell division in germ cells, to produce eggs or sperm (gametes)1 diploid cell 2 haploid cellsGoes through several defined stagesChromosomes are passed on as re-arranged copies due to recombination - creates genetic diversity

Meiosis and RecombinationChromosomes pair upDNA replicationChiasmata formRecombination1st cell division2nd cell divisionGametesResult: meiosis generates new combinations of alleles

The overall processMumDadMeiosisRecombinationEggSpermFertilisationDevelopmentto adult

How much genetic variation?About 35,000 genes in humansIf each gene has only 2 alleles (probably an underestimate), then:Number of possible genotypes = 335,000 = 1016,700Far more than all the atoms in the Universe!Essentially, we are all genetically unique (except identical twins)

RecombinationThe closer together 2 genes are on the same chromosome, the less likely there is to be a recombination between them - such genes are linked and do not segregate independentlyGenes that are far apart are likely to have a recombination between them and will segregate independently - such genes are unlinkedGenes on separate chromosomes are unlinked

Linkage to an autosomal dominant geneAAAaAaaaAaaaAaaaA and a are alleles of a markergeneYellow shading indicates affectedwith a genetic disease (NOT causedby gene A/a)Allele a of the marker gene always segregates with the disease, so the 2 genes must be linked

An application of linkageCan do prenatal diagnosis for genetic disease using a linked geneUseful when you dont know exactly what gene is causing the diseasebb?