Genetics 1 & 2) Genetics, inheritance and populations Flashcards
What are types of genetic abnormalities for disorders?
Single gene (monogenic) Mitochondrial disorder Chromosomal imbalance Polygenic Multifactorial
What is OMIM?
Comprehensive authoritative compendium of human genes and genetic phenotypes
Describe the architecture of a gene
Promoter region
Start codon
Stop codon
Spliceosome enzymes
What are the bases of a promoter region?
TATA
What are the bases of a start codon?
ATG
What are the bases of a stop codon?
TAG
TAA
TGA
What bases usually make up exon-intron boundaries?
GT
AG
What are the classes of mutations?
Deletion - gene, exon, nucleotides
Insertions
Single base substitutions - missense, nonsense, splice site
Frameshift
Dynamic mutations e.g. trinucleotide repeat expansion
What is an autosomal recessive disorder?
Caused by mutations that result in loss of functional gene product
Describe the frequency of cystic fibrosis
Very common in Northern Europe
Carrier frequency is 1 in 23 individuals
Heterozygous carriers are resistant to dehydration so this is advantageous when population experience bouts of water-borne diseases that cause severe diarrhoea e.g. typhoid and cholera
Describe the frequency of Tay-Sachs disease
Common in Ashkenazi jews
History of migration in small population numbers means ancestral Ashkenazi populations experience genetic bottlenecks
What is a genetic bottleneck?
Occur when populations are small enough that genetic diversity is rapidly and randomly lost each generation leading to random fluctuation of allele frequencies regardless of whether they are beneficial or detrimental leading to genetic drift
Describe the frequency of sickle cell anaemia
In malaria endemics, carriers of the mutation have some resistance to the disease
Describe the cystic fibrosis gene
Resides on chromosome 7 and gives rise to cystic fibrosis transmembrane conductance regulator
What is the most common CF defect?
Deletion of 3 nucleotides (CTT) - 508 mutation
Phenylalanine loss at position 508 in CFTR protein so ATT is now followed by GGT
What type of mutation is the CF 508?
Class II
Describe a class I CF mutation
Nonsense / frameshift / splicing mutation
No protein / decreased protein
Describe a class II CF mutation
Missense or in-frame deletion
Block in protein processing
Describe a class III CF mutation
Missense mutation
Defective CFTR regulation
Describe a class IV CF mutation
Missense mutation
Altered conduction of CFTR
Describe a class V CF mutation
Promoter region mutation
Reduced level of normal protein
Describe a class VI CF mutation
Nonsense mutation
Instability at cell surface
Describe the mutation causing phenylketonuria
Mutation affecting enzyme phenylalanine hydroxyls (PAH) which normally metabolises L-phenylalanine to L-tyrosine
Autosomal recessive chromosome 12q22-24.1
What is the consequence of phenylketonuria?
Accumulation of phenylalanine Severe learning difficulties Fair skin Eczema Epilepsy
Describe the size of the PAH gene
79kp
450 different mutations
Mutations mainly in exon 7 compromising catalytic domain
What is consanguinity?
Describes a situation when 2 relatives have offspring
What is the consequence of consanguinity?
Relatives are genetically more similar than non relatives so are more likely to share the same mutations
Means there is a greater chance their offspring will inherit 2 copies of the mutation shared by their parents
What is the inbreeding coefficient for siblings?
1/4
What is the inbreeding coefficient for half siblings
1/8
What is the inbreeding coefficient for uncle / niece?
1/8
What is the inbreeding coefficient for 1st cousins?
1/16
What is the inbreeding coefficient for second cousins?
1/32
What is genomic imprinting?
Mammalian epigenetic process that distinguishes maternal and paternal alleles to ensure parent-specific expression of imprinted genes
Some genes in the allele from one of the parents are inactivated (methylation)
Give an example of an allele only expressed when inherited from the father
The gene encoding insulin-like growth factor 2
What controls methylation of genes?
Imprinting centres located near the imprinted areas on the same chromosome
Give examples of conditions caused by loss of function mutations in the long arm of chromosome 15
Prader Willi syndrome
Angelman syndrome
What is Prader Willi syndrome caused by?
Loss of function in paternal chromosome 15 (deletion of genes in 15q11-13)
What are the clinical features of Prader Willi?
Mental retardation
Hypotonia
Gross obesity (diabetes)
Male hypogenitalism
What is Angelman syndrome caused by?
Deletion in maternal chromosome 15 (15q11-13)
What are the clinical features of Angelman syndrome?
Mental retardation Lack of speech Growth retardation Hyperactivity Inappropriate laughter
What are autosomal dominant disorders?
Those that result from mutations that often manifest in gene products with novel functions or with genes expressed in an unregulated fashion
Give examples of autosomal dominant disorders
Achrondoplasia
Retinoblastoma
What is achondroplasia?
Mutation in fibroblast growth factor receptor 3 gene
Abnormality of cartilage formation
7/8 cases are caused by new mutations
Why is retinoblastoma not expressed in the mother of affected children?
Mother is an obligate carrier
Mutation has a 90% penetrance
What is Huntington’s disease?
Progressive neurodegenerative disease striking later in life
Causes dementia, severe depression and chorea
What causes Huntington’s disease?
Trinucleotide repeat expansion in Huntington gene
What is anticipation?
Age of onset and/or severity is worse in successive generations
What does less than 35 CAG repeats mean for Huntington’s test?
Negative test result
What does 36-39 CAG repeats mean for Huntington’s test?
Uninformative test result
How many repeats are needed for a positive Huntington’s test?
Over 40
What is variable expression?
Individuals inheriting the same mutation can manifest a disorder with varying degrees
What is neurofibromatosis?
Disorder of nervous system, eye and skin
Compare X and Y chromosomes
X chromosome is relatively large spanning over 153 million base pairs and 800 protein coding genes
Y chromosome only has 70 genes
Describe the genetics of Fragile X disorder
X-linked disorder with triplet repeat expansion
Excessive CGG expansion within FMR1 gene
What is Fragile X disorder?
Genetic syndrome that is the most widespread single-gene cause of autism and inherited cause of mental retardation among boys
Describe the range of repeats for Fragile X disorder
Normal range is less than 44
55-200 is known as pre-mutation where there is reduced penetrance
Above 200 CGG repeats is when disorder manifests
What is X-chromosome inactivation / lyonisation?
Females have 2X the magnitude of gene expression as males need to function with just a single X chromosome
Early during embryogenesis one of the female X chromosomes condenses down and becomes inactive - Barr body
What happens to females who inherit a fault gene on the X chromosome that is condensed?
Display reduced penetrance
What happens if mutation occurs in one of the germline precursors as an embryo?
They grow up free of condition as none of the somatic cells have the condition.
However the offspring will have the disorder
Describe the mitochondrial genome
16.5kb
37 genes encoding 13 polypeptides, 22 transfer RNAs and 2 ribosomal RNAs
Give an example of a mitochondrial disorder
Leber hereditary optic neuropathy
What are the types of genetic testing?
Prenatal screening
Newborn screening
Carrier screening
Diagnostic screening, pre symptomatic diagnosis
What are the reasons for genetic testing?
Help diagnose suspected genetic condition
Identify specific underlying genetic change causing a genetic condition
Determine chance of developing a genetic condition in the future
Determine whether someone is a carrier of a genetic condition
Clarify chance of passing a genetic condition onto children
Find out whether a developing baby or embryo has particular genetic condition
What are the methods of genetic testing?
Blood sample from the arm Saliva samples Skin biopsies Amniotic fluid Chorionic villus sampling
What is the function of diagnostic genetic tests?
Identify or exclude specific genetic conditions in an individual who has symptoms or signs of a genetic condition
Often use to confirm a diagnosis
Results can help with healthcare management and provide individuals and families with an explanation for the symptoms experienced
What is the function of carrier genetic tests?
See if an individual is a carrier of the genetic condition as there may be implications for children
When are predictive / pre symptomatic genetic tests done?
When individual has a family history of a serious later-onset genetic condition e.g. Huntington’s disease
Only offered to adults due to need to respect individual autonomy
What are whole exome tests?
New type of genetic testing when you don’t know where in a person’s genetic makeup to look for causes of the condition
Looks at all genes in 1 test
What is chorionic villus sampling?
Offered from 11 weeks of pregnancy
Involves taking a sample from placenta wall with needle through abdomen
What is amniocentesis?
From 15 weeks of pregnancy
Needle through belly to sample amniotic fluid
What conditions can newborn blood spot screening test?
Sickle cell disease Phenylketonuria Cystic fibrosis Congenital hypothyroidism Medium-chain acyl CoA dehydrogenase deficiency
What is the parental conflict hypothesis?
Inequality between parental genomes due to imprinting is a result of the differing interests of each parent in terms of the evolutionary fitness of their genes. Paternally expressed genes tend to be more growth promoting whereas maternally expressed genes tend to be more growth limiting.
