Hereditary 1

Genome

all the genetic information of an individual organism

– Genes: DNA segments that contain the blueprints (coding) for protein synthesis

• Gene expression influenced by interactions with other genes and environmental factors

— complete genetic (DNA) makeup

– Two sets of genetic instructions (maternal and paternal)

Genes

DNA segments that contain the blueprints (coding) for protein synthesis

Genetics

study of the mechanism of heredity (genes = origin)

– Basic principles proposed mid-1800s by Mendel (studied inherited characteristics)

• 100% complete map of human genome achieved in March 2022

– Provides potential to screen and develop personalized genetic disorder treatments

Gametes

• All cells, except gametes, have a diploid number of chromosomes (46) consisting of 23 pairs of homologous chromosomes (one from sperm + one from ovum)

– Homologous chromosomes look similar and carry genes for same characters (e.g., eye color); character variants (e.g., blue or brown eye color) are traits

– Sex chromosomes [1 pair] determine genetic sex

▪ XX = female, XY = male

– Autosomes [22 pairs] guide expression of most inherited traits

karyotype

image of all chromosomes displayed as homologous pairs

Alleles

two versions of the same gene occurring at the same location on homologous chromosomes; interact to determine traits

– DNA sequence can be the same or different

▪ Homozygous: alleles are same for single character (e.g., blood type) (DNA sequence is same on both homologous chromosomes)

▪ Heterozygous: alleles are different

Dominance

one allele suppresses expression of its homologous partner

– Dominant allele denoted by capital letter and recessive by lowercase letter

▪ Example: loose thumb ligaments (“double-jointed”) is a dominant trait, designated as J; tight thumb ligaments is recessive trait designated as j

– Dominant trait is expressed over recessive trait

▪ Example: JJ or Jj will result in double-jointed thumbs

– Recessive trait is expressed only if both alleles are recessive

▪ Example: tight thumb ligaments occur only if person has jj

Genotype

genetic makeup of a person for a trait

– In the loose thumb ligaments example, person can have three possible genotypes: JJ, Jj, jj

Phenotype

physical expression of genotype

– For double-jointed example:

▪ Person with genotypes JJ or jj will have double- jointed thumbs (J is dominant)

▪ Person with genotype jj will not have double-jointed thumbs

Genetic variation

• Each person is genetically unique because of three events:

– Independent assortment of chromosomes

– Crossover of homologous chromosomes

– Random fertilization of eggs by sperm

Chromosome segregation and independent assortment

During metaphase of meiosis I (gametogenesis):

– Two parental alleles of gene (thus trait) segregated (separated) and distributed to two different daughter cell nuclei

▪ Errors in segregation linked to cancer progression and Down syndrome

– Alleles on different pairs of homologous chromosomes are distributed independently of each other, called independent assortment

▪ E.g., Bb is on one chromosome, and Jj is on another chromosome, so possibilities of inheritance are: BJ, Bj, bJ, and bj

– Whether you inherit a B or b is independent of whether you inherit a J or j

▪ Number of different gametes resulting from independent assortment can be calculated as 2^n where n = number of homologous pairs

– In human gametes, =2^23 = 8.5 million combinations!

crossing over

• Genes on same chromosome are linked and can be passed to daughter cells as one unit

• During crossing over (or chiasma), however, homologous chromosomes can break, even between linked genes, and a precise exchange of gene segments can result in recombinant chromosomes

– Chromosomes are now a mixture of contributions from each parent

– Results in tremendous variability

Random fertilization

• Single egg fertilized randomly by a single sperm

• Independent assortment and random fertilization together result in ~ 72 trillion zygote possibilities

– egg possibilities x sperm possibilities = 8.5 million x 8.5 million = ~72 million

• Additional variations introduced by crossing over increase this number exponentially

– Explains why biological siblings are so different

Punnet square

diagram used to predict possible allele (gene) combinations resulting from mating of parents of known genotypes

– E.g., albinism

▪ Dominant allele: A (normal pigmentation)

▪ Recessive allele: a (albinism)

▪ AA and aa are homozygous; Aa is heterozygous

▪ Probability of genotypes from mating two heterozygous parents for albinism:

– 25% AA (normal pigmentation)

– 50% Aa (normal pigmentation)

– 25% aa (albinism)

Dominant recessive inheritance

• Reflects interaction of dominant and recessive alleles

• Predictions are just the probability of offspring inheriting a particular genotype (and thus phenotype)

• Larger number of offspring would increase likelihood of ratios conforming to predicted values

– E.g., if you toss a coin twice, you may get heads both times, but if you toss coin ×1000 , you will probably end up with predicted probability (heads 50% of the time)

• Probabilities can also be calculated mathematically:

– Probability of two offspring having same trait is an independent event

▪ Inheritance in one child does not influence the other

– To obtain overall probability, multiply probabilities of separate events

▪ Example: probability of having two children who cannot roll tongue = ¼ x ¼ = 1/16

Dominant traits

– Dictated by dominant alleles: widow’s peaks, freckles, dimples, double-jointed thumbs, ability to roll tongue or taste phenylthiocarbamide (to name a few)

– Dominant disorders uncommon; lethal dominant genes almost always expressed and result in death of organism before reproductive age

▪ Exception is Huntington’s disease, caused by delayed-action gene that is not activated until age 40∼ (in heterozygous parent)

– Offspring of parent with Huntington’s have 50% chance of disease

Recessive inheritance

– Some recessive genes result in more desirable condition

▪ E.g., normal endochondral ossification is a recessive trait, whereas achondroplasia (abnormal endochondral ossification) is a dominant trait

– Many genetic disorders are inherited as simple recessive traits, such as albinism,cystic fibrosis, and Tay-Sachs disease

– Heterozygotes are carriers of trait (do not express it but can pass it to offspring)

incomplete dominance

– Heterozygous individuals have intermediate phenotype, between those of homozygous dominant and homozygous recessive

▪ May have symptoms, but usually not as intense as those experienced by homozygous recessive individuals

– E.g., inheritance of sickling gene(s); causes substitution of one amino acid in the beta chain of hemoglobin (Hb)

▪ SS = normal Hb made

▪ ss = sickle-cell anemia: only mutated Hb produced, person susceptible to sickle-cell crisis

– Triggered by any condition that lowers their blood 2O (e.g., difficulty breathing or excessive exercise, especially at high altitude)

▪ Ss = sickle-cell trait: both mutated and normal Hb made; person generally healthy, but can suffer sickle-cell crisis if:

– Low blood 2O is prolonged (e.g., traveling in high-altitude areas)

Multiple allele inheritance

– Genes that exhibit more than two allele forms

– Example: ABO blood groups have three alleles: A, B and i

▪ Combination of two out of the three alleles determine person’s ABO blood type

– A and Bare codominant: both expressed if present (type AB)

– i is recessive allele

▪ So, a person with:

– Genotype A and (or and )will have type A blood

– Genotype B and (or and ) will have type B blood

– Genotype A and B will have type AB blood

– Genotype i and i will have type O blood

Sex linked inheritance

– Inherited traits determined by genes on sex chromosomes are sex-linked

– X chromosomes bear over 1400 genes (many for proteins important to brain function); Y chromosomes carry 200 genes∼

▪ Just a few, short homologous regions on ends of Y can participate in crossing over with X

▪ Genes found only on X chromosome are X-linked

– X-linked recessive alleles are always expressed in males, never masked or damped because there is no Y counterpart

▪ X-linked recessive conditions are passed from mothers to sons

–E.g., hemophilia or red-green color blindness

▪ Females must have recessive alleles on both X chromosomes to express X-linked condition

Polygenic inheritance

phenotypes (inherited characters) that depend on several gene pairs at different locations working together

– More common than monogenic inheritance (controlled by single pair of genes)

– Results in continuous (quantitative) phenotypic variation between two extremes

▪ Explains many human characteristics, like skin color, height, metabolic rate, and intelligence

• E.g., skin color

– Dark skin alleles (ABC) are incompletely dominant over light skin alleles (abc)

– First-generation offspring of AABBCC (dark skin parent) aabbcc× (light skin parent) cross would result in all heterozygotes with intermediate pigmentation

▪ Second-generation offspring would have even wider variation in possible pigmentations, which, if charted, would lead to a bell-shaped curve

Mitochondrial inheritance

• 37 of our genes in mitochondrial DNA (mtDNA); transmitted to offspring almost exclusively by ovum because:

– Ovum donates nearly all cytoplasm of zygote

– Sperm m t D N A is selectively destroyed in both sperm and fertilized egg

• Growing list of disorders (all rare) now being linked to mutations in mitochondrial genes

– Most involve problems with oxidative phosphorylation (within mitochondria)

– A few lead to unusual degenerative muscle disorders or neurological problems

▪ Some research suggests Alzheimer’s and Parkinson’s may be among them

Environmental factors

• Maternal factors (e.g., drugs, pathogens) can alter normal gene expression during embryonic development (before birth)

– E.g., use of thalidomide in 1960s

▪ Embryos developed phenotypes (flipper-like appendages) not directed by their genes

– Phenocopies: environmentally produced phenotypes that mimic conditions caused by genetic mutations

• Environmental factors can also influence gene expression after birth

– Poor nutrition can affect brain growth, body development, and height

– Childhood hormonal deficits can lead to abnormal skeletal growth and proportions

▪ E.g., congenital hypothyroidism (results in dwarfism)

phenocopies

environmentally produced phenotypes that mimic conditions caused by genetic mutations