Genes

• eukaryote = the rise of complex life
• genes = carriers of heritable information
• inheritance can occur via somatic and gametic
• Role of telomeres in a eukaryote

  *telomeres stabilise the ends of chromosomes

  *telomeres have a loop structure (T-LOOP) that stops them recombining with other DNA or fusing with other chromosomes

  *telomeres shorten after each round of DNA replication and cell division

  *in embryonic stem and germ cells, the enzyme telomerase prevents shortening of chromosomes during DNA replication
• eukaryote gene = an inheritable sequence of DNA with an associated function contributing towards the phenotype of the organism during development and/or ageing
• eukaryotes have 2 genomes: mitochondrial and nuclear
• The mitochondrial genome:

  *DNA is coated with non-histone protein

  *the DNA is circular and much smaller than the nuclear genome

  *the mitochondria are maternally inherited

  *their inheritance is therefore cytoplasmic
• The nuclear genome:

  *DNA and histone proteins that forms chromatin

  *the fundamental unit of chromatin is the nucleosome

  *Genes are organised into chromosomes

  *inheritance is nuclear
• Main genomic features:

  1. regulatory regions (recognised by factors controlling transcription)
  2. Coding (the mRNA is translated to make a protein)
  3. Non-coding but transcribed (produce RNAs such as tRNA, rRNA or other non-coding RNAs
  4. Intra-genic (DNA sequences within genes- i.e. introns)
  5. Inter-genic (DNA sequences between genes)
• Mitosis v Meiosis

  *mitosis ensures that both daughter cells inherit one copy of the duplicated genome

  -->however, the cytoplasmic material can be

  asymmetrically distributed leading to reprogramming of

  one daughter cell

  *meiosis produces haploid genomes to enable sexual reproduction and increase genetic diversity via recombination
• karyotes = seeing condensed condensed chromosomes at metaphase during mitosis
• Meiosis

  *meiosis follows on from G2 after chromosomes have replicated

  *the chromosomes and chromatids are separated 2 stages to produce haploid cells

  Meiosis I

  -->recombination occurs

  -->homologous chromosomes are separated

  -->produces haploid daughter cells with 2 chromatids

  Meiosis II

  -->divides sister chromatids

  -->equational division

  -->produces haploid gametes with 1 chromatid
• Genetic consequences of meiosis

  *Independent assortment: generates different combinations of chromosomes in gametes

  --> 2^n different gametes can be generated by ID (n= diploid

  chromosome number)

  --> for humans this is 2^23

  *Random fertilisation: 8.4 million possible eggs x 8.4 trillion sperm =~ 70 trillion different zygotes

  *Crossing over: generates new combinations of alleles on chromosomes (non-sister chromatids cross over in prophase I)

  -->humans have 40-95 crossovers per meiosis
• Mendel's Law: monohybrid cross

  1. one gene (locus) with two alleles
  2. mendel's principle of dominance
  3. mendel's principle of segregation
  4. 3:1 phenotypic ratio in the F2
• Mendel's Law: Dihybrid cross

  1. two genes
  2. second Mendel's law: principle of independent assortment
  3. 9:3:3:1 phenotypic ratio in the F2
• Summary of Mendel's theory of inheritance

  *characters are distinct, and hereditary determinants (genes) are particulate in nature

  *each adult has two genes (inherited from mother + father) for each character

  *members of the gene pair segregate equally into gametes, so that each gamete has only one of the two genes (Mendel's first law)

  *fusion of the gametes at fertilisation restores the pair of genes and is random

  *different genes assort independently in gametes (Mendel's second law)
• incomplete dominance = heterozygote phenotype is intermediate between the two homozygote phenotypes
• co-dominance = heterozygotes show phenotype of both alleles
• multiple alleles = there can be more tan two alleles for a gene
• pleiotropy = a gene can influence more than one trait

  (if a specific molecular function of a protein is reused in different cellular contexts, a mutant form of this protein is likely to lead to pleiotropy)
• Lethal alleles = lethal alleles can cause skewed phenotypic ratios
• penetrance = measures the percentage of individuals with a given genotype who exhibit the expected phenotype
• expressivity = measures the extent to which a given genotype is expressed at the phenotypic level
• variable expressivity = gene modifiers can affect the expression of a phenotype
• epistasis = the interaction between two (or more) genes that control a single phenotype
• Main types of epistasis:

  1. one mutation affects the phenotype of another mutation (Reveals how cascade of biochemical reactions are sequentially organised)
  2. Either mutation present no phenotype, but the double mutant has a phenotype (Reveals buffering mechanisms that prevent phenotypic manifestations)
  3. Either mutation have the same phenotype but the double mutant a different phenotype (Reveals prevailing mechanisms that alter phenotypic manifestations)
• Epigenetics = heritable changes in gene expression that do not involve alterations of the DNA sequence of the genome
• Mitotic and epifenetic inheritance of patterns of gene expression:

  *environmental factor switches on expression of red and green genes

  * Expression of the green gene is transient (a) and it is not expressed in daughter cells

  * Expression of the red gene persists through multiple cell divisions (b) – this a mitotic epigenetic effect

  *Environmental factor switches on expression of blue gene in oocyte

  * Expression of the blue gene persists through multiple generations; a meiotic epigenetic effect (rare in animals)
• Chromatin-based modifications causing epigenetic effects:

  *DNA methylation and histone modifications alter chromatin structure

  *Chromatin structure affects gene expression

  *Altered chromatin structure can be passed on to daughter cells

  *Methylated histones and DNA can act as ‘epigenetic tags’ dictating whether genes will be expressed or not
• Genomic imprinting

  Paternal imprinting

  • Paternal allele imprinted and silenced

  • Maternal allele preferentially expressed in embryo

  Maternal imprinting

  • Maternal allele imprinted and silenced

  • Paternal allele preferentially expressed in embryo
• *Prader-Willi syndrome and Angelman syndrome both result from microdeletions in a region of chromosome 15

  Prader-Willi syndrome:

  • Deletion is of paternal origin

  • Maternally genes are intact but

  imprinted (orange) by a methylation (CH3) mechanism

  Angelman syndrome:

  • Deletion is of maternal origin

  • Paternally UBE3A is intact but

  imprinted (red) by a non-coding RNA acting as an anti-sense that silences its expression
• How was genomic imprinting selected in evolution?

  1.Affects a limited number of genes(~80 in humans)

  2. Many imprinted genes involved in foetal growth

  3. The pattern observed is:

  -Paternally expressed genes promote growth

  -Maternally expressed genes suppress growth
• Y chromosome

  *Not all of the y chromosome is male- only 1 gene: SRY (sex-determing region on the Y)

  1. Translocation of SRY to the X chromosome is found in rare XX males (sex reversal)
  2. 2. Mutation of the SRY gene can give XY females`
  3. Transgenic mice expressing SRY will give Most Male Sterile Male rise to males
• SRY is transcripion factor that recognizes specific DNA sequences found in promoters of genes. The binding of SRY at promoters will ac-vate gene expression. Therefore, the effect that SRY confers are conveyed by its target genes
• Sex determination in birds

  • Males are ZZ, females are ZW

  Gynandromorph – a sexual mosaic

  • Cells on the right side of the body have the female sex

  chromosome set (ZW)

  • cells on the left have the male chromosome set (ZZ)

  •Cell-autonomous sex identity (CASI)
• Sex-linked inheritance

  • Sex linked inheritance usually involves genes located on the X chromosome (X-linkage)

  • There are also Y-linked genes, many with male-specific functions (spermatogenesis), but these constitute a small % of sex-linkage

  • Most genes on X are unrelated to sex determination or sex function and are expressed in males and females

  • Males are hemizygous for genes on the X chromosome
• Some X-linked traits in humans

  • Nearly all are recessive and most are in males (hemizygous)

  • ̴ 500 known X-linked disease genes ( ̴ 5% of total disease genes)

  • Haemophilia A (Factor XIII) and B (Factor IX)

  • Duchenne muscular dystrophy

  • Red-green colour vision deficiency ( ̴8%ofmales)
• X chromosome inactivation (XCI)

  • One of the X chromosomes in each female cell becomes inactivated - a type of dosage compensation

  • Inactivated X chromosome becomes highly condensed, does not express genes, and is visible cytologically in interphase as a Barr body
• Random XCI in early development

  • Inactivation starts early in development, is random (affecting either of the X chromosomes) and then persists for all subsequent mitotic cell divisions

  • Consequently female mammals are mosaics with ~50% of cells expressing only the paternal X and ~50% expressing only the maternal X
• A gene map shows us:

  • the relative order of genes on the chromosome

  • the distance between the genes