Of the ___ bps in the haploid genome, < __% encode polypeptides.
3.2 Billion, 2%
There are an estimated _____ genes, but precise annotation is difficult because of ____, ____, etc.
pseudogenes, RNA genes
How did gene families probably originate?
Via gene duplication
Name two categories of gene families.
globin supergene family
How did rRNA genes originate?
How did the globin supergene family originate, and what are examples of them?
Variation in sequences of copies
Alpha and beta globins, myoglobin, and neuroglobin genes
Approximately how many pseudogenes are there?
20,000; possibly more
What are two types of categories of pseudogenes?
Conventional - from mutations that inactivate the gene
Processed - result from a RNA intermediate
Describe DNA transposons.
Use transposase to move, bute nearly all in the human genome are assumed to be inactive; about 3% of the genome.
Name 4 categories of Transposable Elements
Describe LTR Transposons
Originally retroviruses with the gene organization of this viral group; most are currently inactive
e.g. L1. Autonomous, but most do not transpose. Some do since disorders have been linked into insertion of a L1 element into a gene; some make reverse transcriptase; full length copies are about 6.1kb in size, altho many are smaller.
e.g. Alu. 280 bps in length and do not code for any protein; originated as a processed pseudogene (7SL RNA gene); usually inactive unless occupying a fortuitous site in the genome. Many are less than full size and some have transposed int a gene causing a disorder.
Name three types of tandemly repeated noncoding DNA
Describe satellite DNA
large arrays of tandemly repeated DNA; found at centromeres especially (alphoid or alpha DNA, 171 bps in length)
Describe minisatellite DNA
repeated short sequences of 6 to >10 bps with many loci throughout the genome; telomeric DNA consists of a minisatellite of 6 bps; normal function is not clear for most minisatellites but have been useful in some forms of human genetic analysis
Describe microsatellite DNA
short sequences (<10 bps) with many loci scattered throughout genome; 2% of the total genome but function, if any, is not clear
Describe mitochondrial genome
Circular genome of 16,569 bps
37 genes – 13 that encode proteins, 2 rRNA genes and 22 tRNA genes
very gene dense with no introns or repetitive DNA
unique genetic code
Name 4 ways to identify chromosomes
Position of centromere
Comparative Genome Hybridization (CGH)
Describe Giemsa staining
band (400 per genome under standard staining conditions)
Usually heterozygous; most larger ones arise de novo
cri du chat – short arm of chromosome 5
often occurs as a result of unequal crossing over between low copy repeats
Give an example of a contiguous gene syndrome, and what type of chromosomal abnormality is it?
Di George syndrome, deletions of 3 million bps at 22q11.2
Give an example of a Duplication
Charot – Marie – Tooth disease – increased dosage of PMP22 gene on chromosome 17
What are marker chromosomes?
small, “extra” pieces of chromosomes, often detected in prenatal testing of fetal DNA.
What are Isochromsomes?
one chromosomal arm is missing and the other arm has duplicated
What are two types of Inversions?
Describe a paracentric inversion
usually little phenotypic consequences if balanced
crossing over within heterozygous paracentric inversions leads to dicentrics andacentrics and inviable embryos
Describe a pericentric Inversion
Little phenotypic consequences if balanced
Crossing over within heterozygous inversions leads to duplications and deficiencies in recombinant chromatids; some children carrying these defective chromosomes may survive, but have serious defects
Describe Reciprocal Translocations
Adjacent segregation in translocation heterozygotes usually leads to inviable offspring
Alternate segregation leads to balanced gametes
Sometimes 3:1 segregation is found in translocation heterozygotes leading to trisomic or monosomic embryos which is usually lethal
Somatic translocations are often associated with cancer
Describe Robertsonian Translocations
Two acrocentric chromosomes fuse with loss of short arms
Balanced carriers have 45 chromosomes but are phenotypically normal
Carriers with a Robertsonian translocation involving chromosome 21 are at risk for having a Down child
More than 2n. triploid and tetraploid zygotes occur but few survive until birth and those that do die soon afterwards
Not having the normal 46 chromosomes
Quite common occurring in 5% of recognized pregnancies; much higher in spontaneous abortions
All monsomic aneuploid conditions are lethal and the only autosomal trisomic conditions that survive past birth are trisomies 13, 18, and 21
Most aneuploid conditions result from nondisjunction or anaphase lag during meiosis
Mitotic nondisjunction gives rise to mosaic individuals
Describe "simple" Down syndrome
>95% of Down cases are simple trisomy 21
Most cases result from nondisjunction in meiosis I of the mother
Older mothers are at increased risk to have a Down child
Describe Robertsonian Translocation Downs
14q21q and 21q22q are the most common
Down individuals have 46 chromosomes but are trisomic for 21q
A carrier parent (45 chromosomes) is at risk of having a Down child, particularly if it is the mother
This form of Downs can be inherited through several generations
What three trisomies survive to birth
Trisomy 13, 18, and 21
Describe trisomy 13
Occurs in 1/15000 births
Most abort before birth and survival past a few months is rare
Describe trisomy 18
Occurs in 1/7500 births
Most abort before birth and survival past a few months is rare
What is Uniparental disomy?
Both homologues of a chromosome pair come from the same parent
Assumed to start with a zygote that is trisomic for a chromosome – two maternal chromosomes, one paternal chromosome or vice versa
Nondisjuction occurs during early development and by chance a cell results witht wo maternal or two paternal chromosomes; most surviving cells of the individual result from this cell
What is isodisomy?
When the child receives two (different) homologous chromosomes (inherited from both grandparents) from one parent, this is called an heterodisomic UPD. Heterodisomy (heterozygous) indicates a meiosis I error.
What is heterodisomy?
When the child receives two (identical) replica copies of a single homolog of a chromosome, this is called an isodisomic UPD. Isodisomy (homozygous) indicates either a meiosis II or postzygotic chromosomal duplication.
What is the main reason why UPD can lead to a problem?
Gene expression is dependent upon which parent the gene is inherited from
Occurs in the germline and involves changes in histones and DNA methylation
Such changes are reversible and are examples of epigenetics
Give examples of syndromes that can be caused by UPD.
Prader-Willi syndrome (PWS) – both chromosome 15’s come from the mother (30% of the cases)
Angelman syndrome (AS) – both chromosome 15’s come from the father (5% of cases)
What gene determines sex?
SRY gene on Y chromosome determines maleness
Describe the SRY gene.
After 6 weeks the undifferentiated gonads develop into testes if SRY is present andovaries if SRY is not present
SRY produces a protein which has a HMG (high mobility group) box which is aDNA-binding domain which suggests that it is a transcription factor.
Describe the SOX9 gene
The SOX9 gene is one SRY target gene and its expression is upregulated after SRYexpression begins. Duplication of the SOX9 gene causes male development in XX embryos.
SOX9 probably induces or represses several other genes that result in pushing the male pathway. SOX9 expression is reduced in the female pathway.
How many active genes are on the Y chromosome?
Describe features of the Y chromosome.
Contains a major pseudoautosomal region (PAR) at the tip of Yp and a minor PAR at the tip of Yq. These regions have homologous regions on the X chromosome.
95% of the Y chromosome is male-specific and doesn’t recombine with the X.
Yq contains a large block of transcriptionally inactive heterochromatin that varies in size among men.
Genes involved in male fertility found outside of heterochromatin and PAR regions and male infertility is often the result of deletions of some of these AZF genes.
Deletions and point mutations in SRY can lead to XY females.
Describe features of the X chromosome.
The X is a “typical” chromosome with about 1000 genes and, like the Y chromosome, probably evolved from autosomes.
The X is a bit “gene-sparse” but over-represented for genes involved in reproduction and brain function.
Mental retardation is higher in boys than in girls and this is partly due to X-linked mutations in brain function genes.
Describe X Inactivation - Part 1
Occurs early in embryogenesis when the embryo consists of a few hundred cells.
Is reversed in the germline so that eggs will always contain an active X.
It is random as to whether the paternal X or the maternal X is the one inactivated in each cell but once it occurs, all descendents of that cell maintain that choice.
Inactivation is carried out the X inactivation center (XIC) which contains three genes, one of which is the XIST gene
Describe X Inactivation - Part 2
XIST produces a RNA from the chromosome which will become inactive that is nott ranslated and somehow initiates inactivation
The number of X chromosomes in a cell must be “counted” so that only one X is left active, e.g., a XXX cell will have two X chromosomes inactivated
Not all genes are turned off on the inactive X. Some of those that remain active have homologous copies in the PARs of the Y chromosome
Some genes are only partially turned off and gene expression can vary among normal women.
Describe X Inactivation - Part 3
If there is a X with a deletion, it gets inactivated in all cells but this may reflect that only these cells survive
If there is an autosome/X translocation chromosome, it is always active and this may also reflect that only these cells survive
The changes that establish the repressed regions in the inactive X include DNA methylation and histone changes – most likely similar to the changes associated with imprinting
The inactive X chromosome can be seen cytologically as a dark staining body near the nuclear membrane called the Barr body, named for its discoverer. The number of Barr bodies is one less than the number of X chromosomes
What is Turner Syndrome?
Occurs in about 1 in 4000 live female births and only about 50% of Turner women are XO.
15% have an isochromosome for the long arm of the X
What percentage of Turner conceptions spontaneously abort?
Those that are born have mild phenotypes.
What are some characteristics of Turner women?
Turner women are usually infertile with reduced secondary sexual characteristics.
Turner women generally are in the normal intelligence range but many have impaired spatial perception skills
Most XO Turner women obtained their X chromosome from their mothers so nondisjunction or anaphase lag occurs at meiosis in the father
Turner women who get their X from their fathers often have fewer social problems than those who get their X from their mothers; may be an imprinting effect.
Describe XXX females
Occurs in 1 in 1000 live female births
Normal phenotypically and usually fertile
Generally have children with normal karyotypes
Most are in the normal intelligence range but some have reduced IQs and learning problems
Describe Klinefelter Syndrome
Occurs in 1 in 1000 live male births
Tall, infertile with reduced secondary sexual characteristics
Most in the normal intelligence range although some reduction in IQ and many have learning and behavior problems
Describe XYY males.
Results from nondisjunction in meiosis II of the father but occurs at a similar frequency to XXY males that can result from nondisjunction at meiosis I or II in either parent
Tall with some behavior problems and learning disorders in some individuals. Intelligence in the normal range usually
Usually fertile and have children with normal karyotypes
What are aneuploid mosaics?
Zygote may initiate as an aneuploid and then a daughter cell with a normal karyotype may result from a mitotic division or vice versa
Can result from nondisjunction or anaphase lag in mitosis during early development
Testes are present and the tissue is XY but the external genitalia have female characteristics
X-linked recessive gene involved
Infants appear as normal females but testes are usually within the abdomen
Testes secrete testosterone (androgen) normally but there are no androgen receptors so target tissue doesn’t respond and develop into male reproductive structures
Trait vs. Disease
a disease for some may be a trait for others, e.g., deafness
What is penetrance?
Percentage of individuals who have a mutant genotype and express the mutant phenotype, e.g., retinoblastoma has a penetrance of about 90%
What is expressivity?
level of phenotypic expression for a mutant phenotype, e.g., nail-patella syndrome has variable expressivity
Describe Allelic heterogeneity
More than a single mutant allele at a single gene locus which may lead to different levels of phenotypic expression.
Most genes involved in genetic disorders show allelic heterogeneity such as the CFTR gene where over 1000 mutant alleles have been characterized that cause cystic fibrosis.
The only clear example so far of a disorder known to be caused by a single mutant allele is sickle cell disease.
Describe Locus Heterogeneity
More than one gene when mutated gives rise to the same disorder, e.g., deafness and retinitis pigmentosa
Describe Clinical heterogeneity
Even a disorder such as sickle cell disease which has no allelic or locus heterogeneity still shows phenotypic variation which is most likely due to environmental factors and modifier genes.
Leads to the observation that there are no truly simple single gene disorders
Describe Autosomal recessive inheritance
both males and females are equally affected
can be seen more readily if both parents are related (consanguineous marriage)
Autosomal dominant inheritance
doesn’t skip generations unless a new mutation or reduced penetrance is involved
both males and females are equally affected
affected fathers can have normal daughters and affected sons
most dominant mutations are not true dominants, ie., they are incompletely dominant
X-linked recessive inheritance
mostly males are affected
manifesting heterozygotes sometimes appear who are heterozygous women who show the mutant phenotype because of skewed X inactivation
X- linked dominant inheritance
doesn’t usually skip generations unless it is a newly arisen mutation
affected fathers have only affected daughters and normal sons
expect twice as many affected females as males
How can an autosomal recessive allele complicate pedigree analysis?
may be common and not skip generations so it appears as caused by a dominant allele, e.g., blood group O
Pedigree Analysis - reduced penetrance
an autosomal dominant allele may skip a generation
Pedigree Analysis - variable expression
an autosomal dominant allele may give very variable expression so that it is not clear that all affected individuals share the same disorder
Pedigree Analysis - sex influenced disorder
an autosomal recessive allele that is more often expressed in males than females (sex-influenced disorder), e.g., hemochromotosis
an autosomal dominant allele that is expressed only in males (sex-limited disorder),e.g., male-limited precocious puberty where the disorder can be transmitted by normal females
Pedigree Analysis - locus heterogeneity
autosomal recessive conditions with locus heterogeneity where two affected parents have only normal children because two different genes are involved (complementation) e.g., two deaf parents whose children all have normal hearing
Pedigree Analysis - Imprinting
autosomal dominant allele where an individual will be affected or unaffected depending upon whether the mutant allele or the normal allele comes from the father or mother; often the result of imprinting
Pedigree Analysis - Inbreeding
sex-linked recessive allele where inbreeding allows a normal woman who is a heterozygous carrier and an affected man to have both affected sons and daughters
Pedigree Analysis - lethal prenatally
sex-linked dominant inheritance where the mutant allele is lethal prenatally to males so it appears that only females are affected
Pedigree Analysis - new autosomal dominant mutant allele
new autosomal dominant mutant allele arises so that only one individual in the most recent generation is affected; this appears to be autosomal recessive inheritance
Pedigree Analysis - illegitimacy
illegitimacy – sometimes can be detected and accounted for but often not known and can confuse interpretation
Pedigree Analysis - germline mosaicism
germline mosaicism – after one affected individual for an autosomal dominant trait appears among the offspring of normal parents, a second affected child appears unexpectedly
allelic heterogeneity / compound heterozygotes
treatment / screening
Trinucleotide repeat disorders
other trinucleotide repeat disorders
homoplasmy vs. heteroplasmy
Define segmental duplication
Large duplication where the second copy may be located in the same chromosome or an different one; two copies not usually identical
Define compound heterozygote
An individual carrying two different mutations within the same gene making them phenotypically homozygous if the alleles are recessive.
Define sex-limited trait
Trait that is only expressed in one gender or the other but may be inherited as an autosomal or sex-linked trait