L23 - Gene Variation

  1. Genotype-phenotype correlation
  2. Dominance, incomplete dominance & codominance
  3. Inheritance of multiple alleles, including ABO bloodgroups
  4. Observed level of phenotype
  5. Pleiotropy
  6. Polygenic traits
  7. Sex-linked characteristics (& basics of determination)
  8. Mosaicism
  9. Mitochondrial inheritance
  10. Penetrance & expressivity
  11. Gene interaction & epistasis, with emphasis on recessive epistasis (not exact CH2O)*

Complete and Incomplete Dominance

2. Incomplete Dominance

Phenotype of the heterozygote is intermediate between the two homozygous variants


  • Falls within the range of phenotypes coded by either homozygotes

Phenotypic ratio = 1:2:1, same as genotypic ratio in progeny, as each genotype has its own phenotype: an there are 4 possible genotypes

1. Complete Dominance


Transmission of genetic contents to progeny follows Mendelian patterns of inheritance


Therefore the phenotype of the heterozygous, mimics the phenotype of the dominant homozygotes


Dominance thus affects the phenotype which genes produce, but not the way the genes are inherited*

3.Codominance

Expression of both alleles because each are equally as dominant/recessive as the other and both alleles are expressed concurrently


Therefore the heterozygous phenotype is neither intermediate nor dominant, both alleles affect phenotype.


Whereby proteins encoded by both alleles are translated and induce effect

Patterns of Complete Dominance.

  • Complete dominance is an "allelic interaction"
    • Interactions occur between genes at the same locus, but on different chromosomes
    • The products of these genes are both expressed, but at varying levels, and they exhibit varying functionality

  • Dominance influences which genes are expressed, not which genes are inherited

2. Classification of dominance depends on the level at which the phenotype is examined.

Dominance Level and Observed Phenotype

  1. Molecular observations of phenotype
  2. Physiological observations of phenotype
  3. Anatomical observations of phenotype

Type of Dominance (Complete/Incomplete/Codomiance) observed depends upon what level the phenotype is being considered

Polygenic Traits and Disease

Multiple genes working together
produce a continuous distribution of phenotypic effects


These Phenotypes are said to be multifactorial => their expression is influenced by a number of factors (genes + environment)

*E.g. Sickle Cell Anaemia:

Haemoglobin Tetramer of 2 a polypeptide chains & 2 B chains.

  • 4 subunits a =**141 AA each & *B = 146* AA each

In Sickle Cell Anaeamia, single point mutation results in a missense mutation in the protein; Glu => Val in B chain

Polygeneic Inheritance


Individual genes of a polygenic trait follow Mendel's laws, but together do not produce Mendelian ratios.


E.g. Phenotype maybe be influenced by ABC/abc


According to the law of segregation, individual alleles are inherited independently of one another

Sex Determination in Humans


Across different species, different factors determine what sex the organism will assume


  1. Environmental
  2. Social
  3. Genetic (Haploid vs Diploid)

Sex Chromsome Related Disorders

2. Klinefelter syndrome: XXY (also XXXY, XXXXY, XXYY);

  • 1/1000 male births

3. Poly-X females (Multiple X Chromosomes):

  • 1/1000 female births

1. Turner syndrome: X0;

  • 1/3000 female births

Male-Determining Genes


  1. Y chr. sex determining region (SRY gene) causes non-committed gonad to develop as a testis


  2. Other genes on the autosomes also play important roles

  3. Once testes develop they secrete two masculinising hormones
    1. Testosterone (potent androgen)
    2. Müllerian Inhibiting Hormone (MIH)

Sex Differentiation

In early embryo there are* two internal duct systems

  1. Wolffian (male)
  2. Müllerian (female)
    • (MIH inhibits mullerian development)

At 7 weeks, hormonal presence induces sexual differentiation and commitment of undifferentiated gonads

Androgen Insensitivity Syndrome

Caused by defective androgen receptor (unresponsive to testosterone)

Phenotype

  1. External genitalia Appear Female, but they don't have functional ovaries.
  2. They neither have proper development of the internal or external genitalia of either sex

Congenital Adrenal Hyperplasia

Hyper production of masculinising hormones/androgens

Multiple Alleles

When a certain gene is represented by more than 2 alleles

  • a loci may be comprised of two or more alleles (genes) across the population
    • An individual still only has two alleles

The presence of multiple alleles (polymorphism) creates greater varitey of phenotype + genotype

Multiple Alleles in the ABO blood groups

  1. Noted that parents only have two alleles each. These are transmissible across generations
  2. Yet the reality of being more than 2 phenotypes for blood groups necessitates the existence of more than 2 different alleles
  3. Multiple alleles may exist for each gene

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2

Pleiotropy

Most genes have multiple phenotypic effects, aproperty called pleiotropy


  1. This can be seen in human diseases such as
    cystic fibrosis or sickle cell anemia.
  2. In these diseases, multiple symptoms can be
    traced back to one defective allele.

Type of Dominance observed in Sickle Cell Anaemia; depends on phenotypic level of observation

  1. A/A are wild type, RBC never sickle


  2. A/S not anaemic, RBC sickle only under low [O2]


    • Electrophoresis reveals CODOMIANCE at the molecular level
    • Physiological responses indicate COMPLETE DOMINANCE at physiological level
    • Heterozygote has mixture of normal and sickle shaped cells => INCOMPLETE DOMIANCE at the anatomical level
  3. S/S severe anaemia, abnormal Hb & RBC sickle-shaped.

Physiological

Anatomical

Molecular

Codominance, as observed in Blood Group Phenotypes


An example of codominance is found in the variable phenotypes observed on RBCs. Both IA and IB will be expressed simutaneously, resulting in AB blood group phenotype.


  1. IA/IA or IA/i (Geno) => A (Pheno)
    2. IB/IB or IB/i (Geno) => B (Pheno)
  2. IA/IB (Geno) => AB (Pheno)
  3. i/i (Geno) => O (Pheno)

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2

“Bell Shape” curve of degrees. which controls a specific phenotype

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Examples

All of these phenotypes have a genetic link, but importantly are also influenced by environmental effects


=> Multifactorial

Body Type Height

Skin colour

Hair colour

Eye colour

Hypertension

Behavioural traits (alcoholism, phobias)

Cardiovascular diseases

Allergies

Cancers

Diabetes

Intelligence

Y Chromosome

231 protein encoding genes, some unique to Y.

X Chromosome

1500 genes, most don’t have corresponding alleles on Y.

Chromosomal Sex is determined at fertilisation

GonadalSex (Anatomical differences) begin in gestational week 7

Sex is influenced by genetic and environmental factors

MALES

Must secrete both hormone to differentiate into a male

FEMALES

Must have absent levels of MIH and low levels of testosterone to develop into a female
=> Absence of masculinising hormones

4
Blue ring = SRY gene

Hormonal Sex (Prenatal Hormones)

Wolffian Duct

Müllerian Duct

True Hermaphroditism

Generally 46,XX. Appear female, but have ovotestis with both spermatagonia & ovarian follicles (very rare & usually raised as female).

Pseudohermaphroditism

  1. Males are usually 46,XY with insufficient hormone production, phallic hypoplasia.
  2. Female are usually 46,XX but produce high levels of androgenic hormones & exhibit external genitalia masculinisation.