Human genetics (L11)

what is human genetics

the relationship between natural DNA sequence variations and human phenotypic traits

main components of the human genome

22 autosomes, 2 sex chromosomes

diploid

telomeres, long and short arm, centromeres 

diploid - what

2 copies of 22 chromosomes and 1 pair of sex chromosomes (XX or XY)

= 46 chromosomes

telomeres - what

ends of the chromosomes

names of chromosome arms

p (petit) = short and q = long

centromeres

central point between the p and q arms. the two chromosome copies join here during replication

normal karyotype

locus - particular location in the genome

band - a segment within each arm 

ideogram - graphical depiction of chromosome band segments 

chromosome composition 

each chromosome is made up of two strands of DNA in a double helix arrangement 

two metres of DNA per cell 

DNA

each ladder rung has 2 complementary base pairs

nucleotides with sugar-phosphate backbone, and adenine/thymine/guaninecytosine

genes

linear stretches of DNA

main functional units of heredity 

code for a specific functional molecule (RNAs and proteins)

the human genome contains ~23000 protein-coding genes

divided into alternating sequence blocks called exons and introns 

genetic locus

can be a gene, a base pair, or any specific region of DNA 

gene expression

central dogma of molecular biology - genes areexpressed to produce functional RNA and protein molecules 

coding exons make up about 1% of the human genome 

regulation of gene expression

gene promoter: a region of DNA adjacent to a gene that contains binding sites for proteins involved in transcription 

enhancers: upstream regulatory DNA sequences involved in regulating gene expression 

genetic degeneracy

wobble hypothesis - multiple codons can encode for a single amino acid

one tRNA can recognise and bind more than one codon - due to the less precise base pairs that can arise between the 3rd base of the codon at the first base position of the anticodon

allows for the occurence of silent variants

polymorphic loci 

polymorphic loci have several different alleles 

at other loci there is no variation from person to person

genetic marker 

a variable providing information on specific DNA sequence at a particular locus 

disease susceptibility locus

a genetic locus thought to be causal for a particular disease

genetic markers are always observable, whereas a disease susceptibility locus may not be 

genotype

describes a pair of alleles at a locus

heterozygote vs homozygote 

how do genetic variants arise

DNA undergoes frequent chemical change, especially when it is being replicated 

most of these changes are quickly repaired, those that are not result in a mutation 

this a mutation is a failure of DNA repair 

mutations beneficial or harmful

mutations in a population increase biodiversity

can have no effect (neutral), beneficial, harmful (lead to disease or death), mutations that occur in utero can be incompatible with life 

what would happen without mutation 

all genes would exist in one form 

alleles would not exist 

genetic analysis would not be possible

we would not be able to adapt to environmental changes

variants vs mutations

a new genetic variant is created by a mutation during replication or reproduction (an error in replication produces a new type of variant) 

we tend to use mutation to imply a variant that is a genetic marker of disease or associated with susceptibility to disease 

the term mutation refers to both the change in genetic material and the process by which the change occurs 

types of genetic variants/mutations

SNPs and single base substitution 

InDels 

tandem repeats 

structural variants: translocations, copy number variants, inversions 

SNPs - what

most common type of genetic variation among people 

involve base substitutions not a change in the number or rearrangement of base pairs 

SNPs - frequency

1 in 1000 base pairs

most in non-coding regions so wont cause significant changes in phenotype

genetic abberations with high frequency are not typically disase-associated

SNPs are important for population diversity and are useful in identity testing

example of a highly polymorphic locus

human leukocyte antigen (HLA)

a gene complex encoding the major histocompatibility complex (MHC) proteins in humans

HLA genes are highly polymorphoic (many different alleles) allowing them to fine tune the adaptive immune system

what is a DNA haplotype

a group of SNPs and genes in an organism inherited together from a single parent 

represents an individuals combination of SNPs and genes rarely seperated by recombination (tight linkage due to their very clsoe proximity)

first degree relatives, particularly siblings generallu share haplotype blocks 

types of small scale variants

point mutations (single base subs) - silent, missense (non-synonymous), nonsense (premature stop) 

frameshift mutations 

larger repeats (variable number tandem repeats, STRs)

point mutations

single base substitutions

can be silent, nonsense, missense 

non-synonymous (missence) changes can be conservative (amino acid with similar chemistry - tolerated?) or non-conservative

sickle cell disease

results from a non-conservative missense mutations in the beta-glpobin gene

altered proteins results in distortion of red blood cells under low oxygen conditions

consequences of point mutations

gain of function:

increase promoter activity

change amino acid sequence around the enzymes active site 

modify interaction with positive and negative regulators 

outside of gene have little or no effect 

non-coding can change amount 

coding region can change the sequence 

frameshift mutations

InDels can disrupt codon grouping, resulting in a completely different translation 

often lead to premature termination 

can cause loss of amino acids in translated products 

example of a frameshift mutation

tay sachs disease

rare inherited autosomal recessive disorder that progressively destroys nerve cells in the brain and spinal cord 

caused by frameshift mutations in the HEXA gene - makes an enzyme to breakdown things which when they build up cause damage 

copy number variations (VNTRs)

variable number of tandem repeats or short tandem repeats, often called minisatellites - used in forensics 

copy number variaitons - triplet expansion 

e.g. huntingtons disease 

excessive repetitions of CAG nucleotide sequence in a gene 

dominant inheritance 

causes progresseive breakdonw of neurons in the brains 

examples of structural variants 

translocations 

copy number variants 

inversions 

nnondisjunctions 

translocation

movement of a stretch of DNA to a new non-homologous chromosomal location often with no molecular loss

genes at or near the fusion boundaries can become disrupted or may result in formation of functionally fused abnormal gene products (chimeric proteins)

philidelphia chromosome

90% of patients with chronic myeloid leukemia

produced BCR-ABL fusion protein 

changes licalisation of the ABL kinase from nucleus to cutoplasm 

results in the activation of abnormal proliferation and survival pathways 

translocation between chromosome 9 and 22

amplification 

chromosome segment duplicates and reinserts 

this can be adjacent or anywhere in the genome 

deletion

due to a breakage a piece of chromosome is lost

inversion

chromosome segment breaks off, flips around and reattaches 

nondisjunction 

failure of chromosomes to segregate during meiosis

causes gametes to have too many or too few chromosomes 

e.g. turner syndrome (single X chromosome)

down syndrome 

klinefelter syndrome 

gain of function mutation

changes the gene product such that it gains a new abnormal function 

usually have dominant effects and phenotypes 

loss of function mutation

gene products have complete loss of function (amorphic)

haploinsufficiency - one is dysfunctional and the other is not good enough to compensate

lethal mutations

mutations that lead to death

somatic mutation (vs germline)

alteration in DNA occurs after conception

can occur in any of the cells in the body except germ cells

cannot be transmitted to the next generation

somatic alterations can (but do not always) result in harmful disease pathology such as cancer

sporadic

germline mutation (vs somatic)

a heritable change in the DNA (genetic, epigenetic)

occurs in germ cell and is propagated in every cell in the body

can be transmitted to offspring

play a key role in inherited genetic diseases

genetic diseases - what

an illness caused by abnormality in the genome

what is a mendelian trait 

a trait that is controlled by a single locus in an inheritance pattern. a single gene variant can cause disease that is inherited according to Mendels laws

mendels law of segregation

offspring inherit one allele from each parent

parents transmit alleles independently of each other, and within a parent, transmission is random and with equal probability of each allele

can be dominant or recessive 

examples of autosomal recessive mendelian disorders

sick cell anemia - non-conservative missense mutation

tay sachs disease - frameshift mutations 

cystic fibrosis - not a single variant for all cases 

examples of autosomal dominant mendelian disorders 

huntingtons disease - mutation expands CAG in HTT gene 

polycystic kidney disease

myotonic dystrophy 

neurofibromatosis 

sex linked mendelian disorders

hemophilia (X- recessive)

muscular dystrophy (X-recessive) 

rickets (X-dominant)

retts syndrom (X-dominant)

spermatogenic failure (Y)

complex disorders

a variety of environmental and genetic risk factors 

many susceptibility genes 

may have gene-gene and gene environment interactions as well

e.g. heart disease, cancer susceptibility, diabetes, hypertension