First Week of notes Flashcards
Mendelian Laws
1) Law of segregation At meiosis each allele (2 total) of a gene separates so 50% of it goes to a different gamete, 50:50 ratio
Ex: Start with a diploid, double the chromatin so there are 92 chromosomes total (two doubles of 43)
Will ultimately separate via meiosis I and meiosis II into four separate genes
2) At meiosis the segregation of each pair of alleles in >2 genes is independent each 50:50 ratio
Each Gene will independently end up in a gamete
Genotype: The DNA sequence (allele(s)) at a particular locus
o Homozygous: 2 identical alleles at a given locus
o Heterozygous: 2 different alleles at a given locus
o Hemizygous: refers mostly to males (XY), who have just a single copy of each X-chromosomal gene
Basic Definitions in Mendelian Genetics
• Phenotype: The observed/measured trait
• Dominance: A phenotype that is expressed (observed) in the heterozygous state
• Recessive: A phenotype that is expressed only in homozygotes or hemizygotes.
o either aa or an xY (homozygous aa or an x-recessive with the Y)
• Semi-Dominant: When the heterozygous phenotype is intermediate between the two homozygous phenotypes
• Penetranceingeneticsis the proportion of individuals carrying a particular variant of agene(alleleorgenotype) that also expresses an associated trait (phenotype). Inmedical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, if amutationin the gene responsible for a particularautosomal dominantdisorder has 95% penetrance, then 95% of those with the mutation will develop the disease, while 5% will not.
o Penetrance pretty much means how much they will express the gene/phenotype that exists from a genotype (70% penetrance will show the genotype expressed 70% more or will have the disease 70% more)
The pedigree (or family tree) is a graphical representation of the family tree o National Library of Medicine: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.
- proband: (sometimes called the ‘propositus’ or ‘index case’) is the affected individual through whom a family with a genetic disorder is ascertained; may or may not be the consultand (see below)
- The consultand: is the individual (not necessarily affected) who presents for genetic evaluation and through whom a family with an inherited disorder comes to attention
- Consanguinity: identifies cases of genetic relatedness between individuals descended from at least one common ancestor (e.g. first-cousin marriages or even silbings
Inheritance patterns
1) Autosomal dominant Means that one of the two alleles will being primarily dominant
- Ex: XX, Xx, or xx only takes a single X in XX or Xx to have the gene show
- Will see the gene show “vertically” in an inheritance pattern tree, both males and females will have the trait
2) Autosomal Recessive Much more rare, need to have both of the recessive alleles for the gene to show
Example: AA, Aa, or aa
• Need to have the aa for the gene to show, otherwise the A will run rampant over it
• An Aa will be considered a carrier, as they will not show the phenotype/represent the gene, only will carry the “a” with them
3) X-linked Dominant Because the gene is located on the X chromosome, there is no transmission from father to son, but there can be transmission from father to daughter (all daughters of an affected male will be affected since the father has only one X chromosome to transmit).
-With the XX, Xx, or the Xy, xY, it has to an XX,Xx, or an XY
It is IMPOSSIBLE for a man to give it his son, only can give Y gene
• Man can give it to his daughter
-Children of an affected woman have a 50% chance of inheriting the X chromosome with the mutant allele. X-linked dominant disorders are clinically manifest when only one copy of the mutant allele is present.
4) X linked Recessive The disease will only manifest in males, due to the female giving a single x chromosome, and the male having to give a Y chromosome
- X-linked recessive traits are fully evident in males because they only have one copy of the X chromosome, thus do not have a normal copy of the gene to compensate for the mutant copy. For that same reason, women are rarely affected by X-linked recessive diseases
5) Mitochondrial Disease Will only be seen in ALL offspring if mother has the disease
- This is due to all mitochondrial genes coming from maternal inheritance
•Population Genetics–> The study of allele frequencies and how they change in a population
o Four main evolutionary forces affect allele frequencies:
1) natural selection
2) genetic drift
3)mutation
4) gene flow
o Population sampling by phenotype can lead to estimates of allele frequency if the underlying genetic mechanism is known (i.e. dominant vs. recessive // autosomal vs. sex-linked)
♣ It is critical in the case of phenotype, that the disease has a high penetrance
• Remember penetrance is related to how much the allele is expressed (high penetrance= highly expressed gene)
Example: Sad Clown disease with basic populations
♣ 100 people in a class, 1 person has the sad clown disease
100 people in a class, 1 person has the sad clown disease
• Prevelance= 1% (only 1 person has the disease)
• Mutation= 1
We are assuming the disease is a new mutation that could be considered autosomal dominant
• If everyone is cc, then one of the alleles mutated into a dominant C
What is the percentage of the mutant allele?
• 100* 2 alleles= 200 total alleles, than there is a .05% mutation rate or 1/200
Population rate Equation
p2 + 2pq + q2 = 1 can be used to estimate carrier rates
o P^2= the homozygous dominant (AA)
o Q^2= the homozygous Recesive (aa)
o 2pq = the hertozygous (Aa)
Also p+q=1
o Cystic Fibrosis (CF): Prevalence 1:2500
o q2 = 1:2500 q ≈ 1:50
o Carrier rate = 2pq 2(49/50)(1/50) ≈ 1/25
Sometimes it’s helpful to measure allele frequencies and use them to predict genotypes using the Hardy-Weinberg Law
o (alleles) p + q = 1 = p2 + 2pq + q2 (genotypes)
o [p=frequency of common allele; q=rare allele]
o Assumptions:
o Population is large and mating are random
o Allele frequencies remain constant over time because:
1) No appreciable rate of mutation
2) All genotypes are equally fit (equal chance to pass alleles to next generation)
3) No significant immigration/emigration of individuals with different allele frequencies
Most useful information for autosomal recessive diseases in population genetics?
Most useful for autosomal recessive diseases where you want to estimate carrier rates
Applied in genetic counseling situations to tell couples their risk of having a child affected with a particular disease
o Used in genetic counseling to predict risks for a couple to have an affected child
o Prevalence of disease is approximated by q2
o From q2 can calculate q, p, and then the carrier frequency 2pq
The Basic number info of the human genome
3 x 10^9 bp = haploid human genome sequence
Human genomic DNA is distributed on 46 nuclear chromosomes
23 pairs of human chromosomes:
o 22 autosomes (1-22)
o 1 pair of sex chromosomes (XX or XY)
Each chromosome is believed to consist of a single, continuous DNA double helix
o Chromosome number generally based on size:
Chr 1: 245,203,898 bp
Chr 22: 49,476,972 bp
Human genome represents human history, has changed over time as certain areas (such as the Olfactory portion on chromosome 11) have become invalid over time
o Genotype (genome) + Environment = Phenotype o Random variation in a highly ordered structure = almost always deleterious consequences
Genetic diseases from variation–> Price to pay for possibility to evolve with changing genome
Genome Basics of Chromatin
o There are highly expressed regions = eurochromatin
-Chromosome 19 is highly expressed
o There are poorly expressed regions and chromosomes= heterochromatin
Most likely Chromosomes for Trisomies
Chromosome 13,18, and 21 (viable for trisomies)
-Atrisomyis a type ofpolysomyin which there are three instances of a particularchromosome, instead of the normal twoMuch of the chromosomes are stable, unstable regions however are disease associated
-e.g. SMA (Chr 5q13); DiGeorge syndrome (Chr 22q); 12 diseases associated with unstable region on Chr 1 (1q21.1)GC-rich regions (38% of genome), AT-rich regions (54% of genome)
Genome predominance A–T and G–C
- The A-T region is the most dominant
- GC-rich regions (38% of genome), AT-rich regions (54% of genome)
- Clustering (i.e. non-random distribution) of GC-rich and AT-rich regions is basis for chromosomal banding patterns (cytogenetics, karyotype analysis)
Notice that chromosome size does not necessarily mean how much its going to be expressed
Chromosome 19 is smaller, but THIRD most expressed
Finishing the euchromatic sequence of the human genome in 2004
The initial genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps
o It covers 99% of the euchromatic genome and is accurate to an error rate of 1 event per 100,000 bases
-Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods
o The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death
Composition of the Human genome
o ~1.5% is translated (protein coding)
-A tiny portion (roughly 1.5 percent) is actually translated as protein
o 20-25% is represented by genes (exons, introns, flanking sequences involved in regulating gene expression)
o 50% “single copy” sequences
-One gene/one copy
-Does not have multiple copies like repetitive DNA
o 40-50% classes of “repetitive DNA”
-Three major categories of repetitive DNA (Terminal repeats, Tandem repeats, Interspersed repeats)
Current Status of mapping remainder of Euchromatic DNA
Euchromatic regions (more relaxed) and heterochromatic regions (more condensed; more repeat-rich)
o Genome sequencing efforts focused on euchromatic regions
o Heterochromatic regions essentially unsequenced
o Many (>200) sequence gaps still remain even in euchromatic regions
Amount of content for Genome
o Less than 1.5% of genome expresses for proteins, another 5% is regulatory region (promoters, enhancers, ect.)
o Roughly half of the genome is Single-Copy or Unique DNA (roughly 50%)
-Single Copy/ Unique DNA DNA whose linear order of nucleotides is unique
• Much of single copy DNA is still mysterious, as only roughly 1.5% of it encodes for proteins
• Each is roughly several kilobases (several thousand base-pairs)
o Other half of Genome (50%) is repetitive DNA–> DNA whose nucleotides are repeated
Repetitive DNA
• Repetitive DNA for repeated nucleotide sequences, important to note if the repeated sequences in the same location or are interspersed throughout the chromosome
Tandem Repeats A tandem repeat is a sequence of two or more DNA base pairs that is repeated in such a way that the repeats lie adjacent to each other on the chromosome. Tandem repeats are generally associated with non-coding DNA.
• Tandem repeats are called “tandem” becase the repeated sequences start head to tail of one another
♣ Satellite DNA different types of Tandem Repeats, these are large arrays of repeating nucleotides
• Alpha Satellite DNA repeating DNA in centromeres
Dispersed Repetitive Elements Instead of being on a specific chromosome or several locations, these are repetitive DNA that’s throughout the genome (on multiple chromosomes)
2 Major families of Dispersed repetitive elements
• ALU family a type of dispersed resistive element seen on many chromosomes, they are a repeating 300 base pairs
o At least a million different Alu families
o Make up 10% of the genome
•LINE (Long interspected Nuclear Elements) The second major dispersed component of repetitive DNA, is roughly 6 kb long (6000 base pairs)
o Roughly 850,000 copies per genome and makes up 20% of the genome
2 Major families of Dispersed repetitive elements
Dispersed Repetitive Elements Instead of being on a specific chromosome or several locations, these are repetitive DNA that’s throughout the genome (on multiple chromosomes)
• ALU family a type of dispersed resistive element seen on many chromosomes, they are a repeating 300 base pairs
o At least a million different Alu families
o Make up 10% of the genome
• LINE (Long interspected Nuclear Elements) The second major dispersed component of repetitive DNA, is roughly 6 kb long (6000 base pairs)
o Roughly 850,000 copies per genome and makes up 20% of the genome
Tandem Repeats
Type of repetitive DNAo Tandem Repeats A tandem repeat is a sequence of two or more DNA base pairs that is repeated in such a way that the repeats lie adjacent to each other on the chromosome. Tandem repeats are generally associated with non-coding DNA.
• Tandem repeats are called “tandem” becase the repeated sequences start head to tail of one another
Satellite DNA different types of Tandem Repeats, these are large arrays of repeating nucleotides
• Alpha Satellite DNA repeating DNA in centromeres
SNPs (Single Nucleotide Polymorphism)
o A change in one in every 1000 nucleotide base pairs, will change between an A—T or an G—C
Occur more often in non-coding genome
Can have consequences in coding genome such as changing a codon to a stop codon and such