Week 3 Genetics, genetic inheritance, and congenital disorders

nucleus

contains almost all genetic information (minus DNA from mitochondria) in the form of chromatin

chromatin

DNA and chromosomes are found within, highly concentrates into chromosomes during cell division, chain like sequence of nucleosomes

histones

proteins that combine with DNA to make up chromatin (gets spooled around twice)

nucleosome

structure that is formed when DNA wraps around histones

positively charged

charge of histones

negatively charged

charge of DNA

effects of spooling

repression of gene expression, effectively regulates which genes are expressed and which are not

histone modification types

acetylation(HAT), HDAC, methylation

acetylation (HAT)

allows for the activation of a gene

HDAC

deactivates the gene

methylation

complex form of regulation, typically inhibitory

histone modification implications

embryology; epigenetics; heritability

euchromatin

“good” chromatin, active with promotor regions released from histones (minimally staining)

heterochromatin

inactive, tightly spooled, darkly staining

genes

sequence of DNA that contain the intructions for making a protein

transcription

DNA to RNA

purines

adenine, guanine

pyramidines

thymine, cytosine

RNA polymerase

makes new RNA

RNA polymerase I

makes ribosomal RNA

RNA polymerase II

contains mRNA elements, some dsRNA (ex: siRNA- short interfering RNA)

RNA polymerase III

makes tRNA, some rRNA

promoter DNA sequences (TATA, GC “boxes”)

where transcription starts

5’ to 3’

direction of transcription

transcription factors

regulate transcription, proteins that may be necessary for slowing or speeding up transcription but are not directly part of the process

nucleus (not the cytoplasm!)

site of transcription, mRNA copy of the gene is sent out to the cytoplasm

DNA splicing

removal of non-coding sequences in the DNA (introns) and potential rearranging of exons left behind allows for multiple different genes from the same DNA sequence- splice variants

redundancy in amino acid assembly

multiple codon sequences create the same amino acid, allows for increased efficiency during transcription and translation (allows for more errors)

translation

in the cytoplasm, mRNA acts as the pattern and is held in the ribosome, which then lines up tRNA with the corresponding amino acid, leading to a building of an amino acid chain, creating a protein

untranslated regions (UTRs)

mRNA contains these portions, may be involved in regulatory functions

polypeptide chain

amino acid chain

secondary structures of polypeptide chains

alpha helices, beta sheets

tertiary structure of protein

may have additional post translational modifications, such as phosphorylation, glycolation, lipidation, creating one subunit

quaternary structure

built of multiple tertiary structures

effects of exercise

perturbation of homeostasis, acute rapid responses and potentially genetic, long term change (due to post translational modifications)

genetic response to exercise

acute responses mostly post-translational, modify responses of existing proteins, does increase transcription

Response to exercise

Graph shoes how antioxidants result in less citrate synthases activity after exercise training, as opposed to a group who did not take antioxidants- antioxidants inhibit the signal produced by the increased need for mitochondria (the increasing levels of free radicals)

training-induced increase in many proteins

increases in mRNA often coincides with this, not the only factor though and not typically 1:1

lower baseline level of transcription

tends to induce larger, more rapid increase in transcription

higher baseline of transcription

tend to be associated with smaller, slower, more sustained responses

summary of genetic response to exercise

transcription factors, structural and metabolic gene increases, acute increase in transcription

protein turnover

basis for most exercise adaptations- balance of degradation and synthesis

half life equation

change in T = -ln(0.5)/k so half of the protein will degrade in 0.693/k

concentration

the rate of degradation is dependent on this factor, it takes about 5 half lives to get to 3% above baseline

5

number of time constants is takes to hit plateau of increase in protein

1

number of half-lives it takes to lose 50% of what you gained in 5 half-lives (why detraining is more rapid than training)

epigenetic memory

change in gene expression and phenotype is “remembered” by the cells- this makes training again after a break easier- makes a faster and/or greater response to return to training

cell division uses

tissue growth and repair, reproduction, possibly adaptation, mitosis, meiosis

S phase

phase in which DNA duplication occurs, DNA synthesis occurs antiparallel 5’ to 3’

congenital disorders

are present at birth, may have been substantially ahead of birth, and may or may not be genetic in origin

exogenous congenital disorders

genetic disorders that arise due to environmental factors, are not written within the genome

endogenous

congenital disorder than is written within the genome

chromosomal genetic disorders

excess of deficiency of genes in chromosomes or chromosomal segments, many not viable, accounts for half of all spontaneous 1st trimester abortions and 7/1000 liveborn infants

single gene defects

individual mutation of a gene, affect about 2 percent of population over lifespan

multifactorial genetic disorder

account for most genetic diseases, genetic component increases risk and there is a degree of heritability, don’t follow single-gene patterns, and as an estimate affect about 60% of the population

cancer, alzheimers

examples of multifactorial genetic disorders

endogenous enzymes

are used to correct or remove errors made during transcription and translation (gene editing), examples include DNA ligases, nucleases, RNAases, regulatory RNA (siRNA, dsRNA)

clinical application of endogenous enzymes

DNA ligases, nucleases, RNAases, regulatory RNA are now being used to edit genes in research labs and increasingly in clinical applications

RNAi knockout

RNA regulatory, delivered into animal to knockout a specific gene, sometime has an affect, sometimes does not!

mutations

mistakes made in replication that are not fixed, more are inconsequential but others that happen during meiosis/gameteogenesis can lead to genetic disorders in offsprings that are not present in the parents

punnet square

show one generation, a single gene autosomal probability of the next generation inheriting specific traits

pedigree

family history, shows multiple generations, may or may not follow Mendel’s principles, shows what happened (who was affected, who was unaffected)

independent assortment

gets own punnet square, when genes are split up the genes aren’t influenced by other genes, split into the gametes independently of each other

segregation

when the alleles separate during meiosis

dominance and recession

dominant trait is expressed over recessive, recessive only shows if with another recessive gene

homozygous

when all of your copies of a gene are alike

heterozygous

when you have two different copies of a gene, if you carry a recessive trait and don’t show it you are a carrier

hemizygous

when you only have one copy of a gene

genetic diseases

when mutations persist and can be passed down to progeny- examples are cystic fibrosis, huntington’s disease, niemann-pick disease

SNP

single nucleotide polymorphism, one amino acid difference, a single base exchange that causes a mutation- sickle cell disease is an example

genotype

a peron’s genetic material

phenotype

a person’s physical characteristics

white blood cells

where chromosomes are collected from in blood samples

karyotype

complete, organized visual profile of a person’s chromosomes (have 46, 23 pairs normally)

aneuploidy

when problems in chromosome duplications occur, this may occur- problems with the number of chromosomes that an individual has

monosomy

having only one chromosome instead of the normal pair

polysomy

having multiple chromosomes (more than 1) in a set

trisomy

having three chromosomes in a set of chromosomes

viable trisomies

13, 18, 21, X, Y

monosomy X

viable but may carry issues, only one X chromosome, aka turner’s syndrome

most common trisomy (and viable)

trisomy 21 (down’s syndrome)

non-disjunction

when there are problems during separation and segregation of the chromatids during meiosis- leads to multiple or no chromatids per gamete

deletion

chromosomal structural defect that occurs when there is a segment of the chromosome lost

inversion

chromosome structural defect that occurs when portions of the chromatid switch positions along the chromatid

isochromsome formation

chromosome structural defect that occurs when the chromosome splits horizontally instead of vertically when separating into chromatids

ring formation

chromosome structural defect that occurs when ends of the chromatid come off as fragments, and the new ends of the chromatid fuse together and make a ring

translocation

chromosome structural defect that occurs when portions of the chromatid are transferred to each other (is often normal during crossing over in meiosis)

single gene disorders

in theory, follows mendelian rules related to dominance and recessive-ness, may be autosomal, sex-linked, dominant, or recessive though

penetrance

the proportion of genotype that manifest phenotype (any aspect) even if dominant, may be a result of the environemnt

expressivity

range of clinical features that occur in an individual with a particular genetic condition

marfan’s syndrome

autosome dominant disorder of the connective tissues, has complete penetrance (every individual will show something), but has widely variable expressivity (how much they will show it)

gaucher disease

autosomal recessive variant of GBA disease, estimated 40% penetrance

polymorphism

having greater than two phenotypes, from codominance (ex blood type) or incomplete dominance

epistasis

genotype of an unrelated trait effects the expression of a different trait (ex the black, chocolate, or yellow labs)

quantitative traits

measurable, numerical characteristics like height or weight that vary along a continuous scale. They are influenced by multiple genes (polygenic inheritance) and environmental factors, resulting in a range of phenotypes. This combination of genetic and environmental influences creates the continuous variation seen in populations for traits such as milk production, weight, and blood pressure

discrete traits

observable characteristics that fall into distinct, separate categories with no intermediate forms, rather than existing on a continuous spectrum.

mosaicism

different genomes in different cell populations in one person, timing and nature can alter the phenotype, dominance and recessivity patterns may be different in different cells- won’t be detected if correct cell type isn’t tested, may play an important role in cancers

post-fertilization mosaicism

chromosomal alterations that occur during cell division of zygote/embryo, results in having different cells with differents sets of genes, can result in aneuploidy, the earlier it occurs, the more likely it is to affect more of the body

mitochrondrial genetic disorders

frequent example of mosaicism, since they come from the mother and the mother has more than 2, she may pass several different mitochondrial allele to the child (also if mutations aoccur here they can be passed down)

mulitfactorial (complex) inheritance

impact of various environmental factor on certain genotypes, has some genetic components like heritability or relative risk