Human Genetics

1/21/2025

What is a genome?

• all genetic information contained in a cell

• 3gbp for a haploid cell (but we have 2 copies so really 6 GBP)

  • Males actually have 6.27 GBP

  • Females actually have 6.369 GBP

  • Because Y chromosome is shorter

Genes

• Gene: Basic physical and functional unit of heredity

  • Has to do something (encodes for a protein or other product like tRNA or rRNA)

• Knowing what parts of the genome are functional lets us understand genetic disease

• Humans have about the same number of PCGs as nematodes

  • Humans have many more mRNAs than protein-coding genes

    

• Eukaryotic gene structure

  

  • Pre-mRNA contains functional elements not present in mature mRNA

Chromosomes

• 2 kinds (autosomes and sex chromosomes)

  • Distinguished because inherited diseases from sex chromosomes have different behaviors

• We have 22 autosomes and X and Y sex chromosomes

  • Each autosome comes in two different versions in all your somatic cells — so 44

  • Plus XX or XY

  • Plus Mitochondrial

  • So we have 47 chromosomes

• Chromosomes are numbered in order of length (longest to shortest)

• Karyotype: picture of chromosomes in an individual

  • Take cells, grow them, and treat them with chemicals that cause them to arrest at the condensation stage

    • Isolate the chromosomes and try to match them up

      

• Each chromatid is a single DNA molecule

  • Two identical chromatids make a chromosome

    

• Chromosomes in the cell cycle

  

  • Checkpoints ensure chromosomes are made

  • In beginning of S phase, chromosomes have centromeres but aren’t paired

  • In late S phase, there are two DNA double helices per chromosome

  • In M phase, sister chromatids separate to give two chromosomes that are distributed into two daughter cells — you need 2 sister chromatids to divide

• Chromosomes are critical to the accurate transmission and regulation of genetic information

• Chromosomes are fundamental to the generation of variation

• Incorrect meiosis, mitosis, or mutation can result in abnormal genetic composition

• Stained chromosomes can be visualized and studied for major changes in chromosome structure

Chromosome structure

• Types of chromosomes

  

  • The first chromosome has 2 sister chromatids, the second one only has 1 chromatid

  • Centromere can be used as a landmark to describe the location of genes

    • P arm (short) and Q arm (long)

    • Chromosome is never in the exact center

      

  • As the centromere goes to the end of the chromosome, the number of genes in the p arm goes down

    • Acrocentric chromosomes tend to have special functions (13, 14, 15, 21, 22)

• Homologous chromosomes: one came from mom, one came from dad.

  • NOT IDENTICAL

• Mitosis

  • Homologs do not pair

  • Sister chromatids separate during anaphase

  • The daughter cells are diploid (2n) like the parent cell

• Meiosis

  • Meiosis I: Homologs pair and separate — recombination happens here

  • Meiosis II: Sister chromatids separate

  • Reduction division: the parent cell is diploid (2n), the daughter cells are haploid (n)

• KNOW MEIOSIS AND MITOSIS

Meiosis I

• Metaphase I: Homologs pair (p-p, q-q all along the chromosome)

  • Homologous chromosomes are driven to pair up

  • Crossing over also happens here (non-sister chromatids exchange genes from one homolog to another). It happens on average once every meiosis for each arm for each homologous pair

    • Recombination happens in a sequence-specific manner

      

• Anaphase: recombined chromosomes get pulled apart

  

Meiosis II

• Chromatids are separated out so gametes have only 1 set of chromosomes

  

Spermatogenesis and oogenesis

Independent assortment

• Genetic variation can be generated via independent assortment

• Happens when homologs line up on the metaphase plate

• A chromosome does not influence B chromosome

  

• How are there so many combinations?

  

  • 2²³ different sperm, regardless of recombination

  • Recombination

  • Mutation

  • Incorrect meiosis

Numerical chromosome abnormalities

• Polyploidy: Extra whole sets of chromosomes (dispermy of fertilization of diploid cell)

• Aneuploidy: one or more chromosomes extra or missing (non-disjunction)

  • Disomy: two copies of a chromosome, the normal state for most human cells

  • Trisomy: 3 copies of a chromosome

  • Monosomy: one copy of a chromosome

  • Mosaicism: when two cell lines with different karyotypes exist in a single organism

• Mixoploidy: Two or more cell lineages mixed (mosaicism or chimerism)

• Non-disjunction:

  • Most aneuploidies result from meiosis I errors

    

    • You end up with a cell with no chromosome, and a cell with both homologous chromosomes

    • In the second division, two gametes end up with 2 chromosomes (one mom and one dad), and two end up with nothing

  • In meiosis II errors, two gametes end up normal, one ends up with 2 identical chromosomes (both from mom or dad), and one has nothing

Chromosome mutations

• There are commonly humans with translocations

• In reciprocal translocation, nothing is lost or gained as long as the breakpoint doesn’t disrupt the function

  • Produces 2 complete chromosomes, they just don’t look how they are meant to

• The drive for homologous chromosomes to pair is sequence-based

• When there is a translocation, pairing up gets weird

  • Normal and balanced translocation will lead to a normal zygote

    • Leads to translocation carrier

  • Duplicated and deficient = some areas are duplicated while others are missing

1/23/2025

Origins of polyploidy

• fertilization by 2 sperms

• doubling chromosomes but not dividing (endomitosis)

• euploid=normal

Fluorescence in situ hybridization (FISH)

• Good for quick chromosome count, detection of known/suspected deletions/deletions

• Quick turnaround (24-48 hrs)

• Limited bu probe availability

• Targeted

Microarray analysis

• A way to measure the quantity of a given sequence of DNA in a sample

• Can be used to detect full or partial aneuploidy including mosaicism

• Standard testing during initial work up for a person suspected to have a genetic syndromeX$

• Doesn’t work on translocation

  

Nomenclature

• 46, XY = 46 chromosomes, male (normal)

• 47, XY+21 = 47 chromosomes, male, trisomy 21 (downs syndrome)

• 46, XX, del(22)(q11.2) = 46 chromosomes, female, deletion on chromosome 22 at band q11.2 (digeorge syndrome)

  

Common aneuploidies

• Trisomy 21 (Downs syndrome)

• Trisomy 18 (Edward syndrome)

  • Characterized by small size, unusual ear shape, small jaw, heart defects, usually lethal

  • Partial or mosaic form may be milder

• Trisomy 13 (Patau syndrome)

• Monosomy X (turner syndrome)

• XXY syndrome (Klinefelter syndrome)

• Trisomy 16

• Triploidy

  • An extra copy of every chromosome

  • Most common polyploidy in humans

  • Lethal in non-mosaic state

  • Most commonly caused by diandry

Case studies

1. You are asked to evaluate Lucy, a 14 month-old girl with a history of

   microcephaly, dysmorphic facial features, and developmental delays. In reviewing her family history you learn that she has two siblings both of whom have intellectual disabilities

   • You order a microarray for Lucy and get the following result...

     • She has a 9.4 Mb gain on the p arm of chromosome 4 (partial trisomy) and a 6.8 Mb loss on the p arm of chromosome 8 (partial monosomy)

     • Seems like one of her parents had a translocation — she had a duplicated and deficient zygote

   • You then order a karyotype of the parents

     • Dad is 46, XY

     • Mother is 46, XX, t(4;8)(p16;p23)

       • Translocation in 4 and 8 at breakpoints 16 and 23 respectively

       • But she’s normal because she has all of her genes (translocation heterozygote)

       • Transfer of chromosomal regions between non-homologous chromosomes has an incidence of 1/500

         

• The couple wants to have another child. What are their options?

  • Reproductive options

    • In Vitro fertilization with preimplantation genetic diagnosis

    • Gamete donation

    • Adoption

    • No kids

  • Post conception options

    • ultrasound

    • Chorionic villus sampling

    • Amniocentesis

    • Cell-free fetal DNA analysis

Translocations

• Balanced: No gain or loss of genetic material at the translocation breakpoints

• Unbalanced: Some gain or loss of genetic at the translocation breakpoints;

  this may result in phenotypic anomalies

• Translocation Carrier: an individual who carries a balanced chromosome

  translocation; phenotypically normal (unless the breakpoints disrupt gene

  function)

• Origin of Translocations

  • Inherited: translocation carriers may pass the balanced (or unbalanced) form of a translocation onto their offspring

  • De Novo: a balanced or unbalanced translocation may arise through recombination in non-sister chromatids during (meiosis) or shortly after conception (mitosis)

• Autosomal Reciprocal Translocation:

  • The exchange of segments between two non-homologous (heterologous) autosomal chromosomes

  • Balanced carriers are generally unaffected

  • Miscarriage risk: 20-30% on average for female carriers (but this varies greatly by translocation

• Sex Chromosome Translocation:

  • The exchange of segments between one sex chromosome and another chromosome

  • The second chromosome may be an autosome or a sex chromosome (rare)

  • Generally causes infertility

• Robertsonian Translocation: the fusion of the long (q) arms of two acrocentric

  chromosomes (13, 14, 15, 21, 22); the short arms (p) are lost

  • Heterologous Robertsonian: A Robertsonian caused by the fusion of the q arms of two different acrocentric chromosomes

  • Homologous Robertsonian: A Robertsonian caused by the fusion of the q arms of two copies of the same chromosome

    

    

• Impact of translocations

  • Unbalanced translocations

    • Generally cause birth defects and intellectual disability

    • The larger the monosomic/trisomic segment the more severe the phenotype

  • Balanced translocation carriers

    • Generally healthy unless one of the breakpoints disrupts a gene

    • 20-30% risk for miscarriage with each pregnancy but may be as high as 50+% (general

      population risk is 15%)

    • The risk for miscarriage is generally higher if the translocation carrier is female

    • Males are at risk for oligospermia\

    • If a balanced de novo translocation is identified prenatally there is a 6% risk for an abnormal phenotype in the baby

IVF with PGD

• IVF: collection of sperm and egg samples allowing for fertilization outside the uterus, promising embryos are implanted in the mother

• PGT-A: testing done on embryos at the 8-cell stage, frequently via FISH, to look for imbalance, only balanced (normal or carrier) embryos are implanted

CVS and amniocentesis

• Amniocentesis: 1/300 wish of miscariage, tests amniotic fluid

• CVS: chronic villi, 1/100 risk of miscarriage

• FISH may be used to obtain a preliminary result. Microarray is fast replacing karyotyping as the standard of care for prenatal samples

• Cell-free fetal DNA analysis

  • Analysis of cell-free DNA in maternal circulation to assess for fetal aneuploidy

Case study 2

• You are asked to see Pamela, a 27 year old pregnant woman who is currently

  19 weeks. She had her fetal survey at her obstetrician’s office and the baby

  was noted to have short long bones, an absent nasal bone, and pelviectasis.

  She will be meeting with you prior to her targeted fetal anatomy ultrasound

  to discuss the findings and her options. Her husband, Trevor, accompanies her

  today

  

• They opt for an amniocentesis

  • Result: 46, XY, rob(21;21),+21

  • Rob=robertsonian translocation (acrocentric, one chromosome is twice as long)

    • Leads to Down syndrome

• They then opt for karyotyping

  • Pamala is 45,XX,rob(21;21)

  • This means she has just 1, really long 21st chromosome

  • She will always have nondisjunction — can only make gametes with no chromosome 21 and ones with 2

    

1/28/2035

Mendelian genetics

• Key concepts

  • Inheritance of a characteristic follows mendel’s rules if its presence or absence is determined by the genotype at a single locus

  • Mendelian characteristics can be dominant, recessive, or co-dominant. A characteristic is dominant if evident in a heterozygote

  • Human Mendelian characters give pedigree patterns that are often recognizable

• Most characteristics are actually polygenic (multifactorial)

  

• Variable expressivity: a trait or disease can manifest differently among affected individuals

• Phenocopy: a phenotype that mimics the trait of interest but does not share the genetic etiology

• Disease alleles of genes are rare

  • Subject to certain conditions, allele frequencies and genotype frequencies are related by the Hardy-Weinberg formnalle=a

  • p+q=1

  • p²+2pq+q²=1

Inheritance patterns

• Autosomal recessive

  • Usually only one generation affected

  • Carriers are not affected

  • No association with sex

  • Children of a carrier couple are at 25% risk

    • Unaffected children have a 2/3 chance of being a carrier

  • Parents of a recessive child are obligate carriers

  • Consanguinity increases the risk for AR conditions

    • Fancy word for incest

  • Examples

    

• Autosomal dominant

  • Multiple successive generations (but may arise de novo)

  • NO association with sex

  • Children of an affected individual at 50% risk

  • Examples

    • Huntington’s disease

    • Treacher Collins syndrome

• X-linked

  • Multiple generations affected

  • Males tend to be more severely affected than females

  • Can be dominant or recessive but usually there is a broad spectrum

  • All daughters of affected males will be caries/affected

    • No male-male transmission

  • Each child of an affected female is at 50% risk

  • Examples

    

  • Pedigree is maybe a little unexpected — Mosaicism makes it so that women

    will sometimes express the diseased X

    • Which X (the paternal or maternal copy) is chosen for inactivation in an XX embryo is determined randomly and independently by each cell of the embryo, at the 10-2 cell stage

    • However, once a cell has chosen which X to inactivate, that X remains inactive in all its daughter cells

      

    • Barr bodies

      • XY males keep their single X active (no Barr body)

      • XX females inactivate one X in each cell (one barr body)

      • Females with turner syndrome (45,X) do not inactivate their X (no Barr body)

      • Males with Klinefelter syndrome (47,XXY) inactivate one X (one Barr body)

      • 47,XXX females inactivate two X chromosomes (two Barr bodies)

• Y-linked

  • Only present in Males

  • Only male-male transmission (females cannot be carriers)

  • All sons of affected male will be affected

  • Super rare

  • Example

    • Spermatogenic failure

• Mitochondrial

  • All affected children of an affected female will be affected (regardless of sex)

  • Affected fathers will not have affected children

  • Significant variation in severity with a tendency to get worse with each generation

  • Mitochondrial diseases caused by mutations in the nuclear genome follow an autosomal pattern of inheritance

    

  • Mitochondrial genes

    • MELAS

    • Leigh syndrome (also in nuclear genome)

  • Example: mitochondrial myopathy

  • Treatment

    • Mitochondrial replacement

Mendelian characteristics vs genes

• Locus heterogeneity: Sam clinical phenotype from mutations at any one of several different loci. Also called clinical heterogeneity

  

• Allelic heterogeneity: different mutations at the same locus result in the same clinical phenotype i.e. different mutations in the same gene may cause loss or gain of function leading to a specific mendelian disease

Mendelian complications

• Non-paternity

  • When the stated after is not the biological father

  • May be uncertain

  • Difficult to address with families

• Ascertainment bias

  

  • Not ¼ but 8/14

• Common recessive looks like a dominant

  • O is recessive but also really common

    

• Non-penetrance

  • Parent has condition but it doesn’t show up in the phenotype

• New mutations and mosaicism

Key concepts

• Gonadal mosaicism

  • When the gamete population of an individual is mosaic for an allele

  • Can cause an unaffected individual to have multiple children with an autosomal dominant condition

    

  • Chimerism

    

1/30/2025

Case study 1

• You are as ked to evaluate Alex, a 2 year old boy with a history of easy bleeding and bruising. As the family is very wealthy and influential you agree to make a house call. At the family home you meet Alex’s parents, Lexi and Nick, and his four older sisters. Lexi repor ts the following family history

  

• Hemophelia is x-linked, however about half of cases result from de novo mutation

• Deficiency of clotting factors 8 and 9, found at F8 and F09 genes

  • Locus heterogeneity

• You can test factor 8 and 9

  • Not able to diagnose 90% of female carriers

• Female carriers can be symptomatic and may be at-risk for bleeding especially during childbirth

Case study 2

• Maryann, a 45 year old woman, comes to yo ur clinic to request testing for a familial condition that causes dementia and involuntary movements . She reports that her father w as diagnosed at age 63. Her brother was also diagnosed 5 years ago

  

• Huntington is autosomal dominant and found on chromosome 4

  • Caused by a CAG repeat expansion in the HTT gene

  • 3 nucleotides are repeated over and over again — highly unstable

  • Normal alleles: 26 or fewer CAG repeats

  • Intermediate alleles: 27 – 35 CAG repeats; will not develop HD but

    may have children with HD due to anticipation

  • Reduced-penetrance alleles: 36 – 39 CAG repeats; some individuals

    in this range will never develop symptoms

  • Full-penetrance alleles: 40+ CAG repeats; 60+ CAG repeats may

    result in juvenile HD

  • Increasing repeat size is associated with earlier onset of symptoms

  • Easy to test for

• How did we figure out where the huntingons’s allele was?

  • Crossing over

  • Need a lot of families where the disease incidence is high

  • In one part of venezuela, there was a small founder population, and now the incidence rate is 1/125

Case study 3

• Omar and Nadia come to your clinic to discuss a family history of intellectual disability and dysmorphic facial features. Nadia is 28 weeks pregnant

  

  • Autosomal recessive

  • Consanguinity increases the chance for homozygosity by descent

  • Everyone has about 5-7 deleterious recessive alleles

  • Consanguinity increases the chance to have a child with an autosomal recessive condition

  • Increases the risk for birth defects that are not part of a

    known genetic syndrome

Case study 4

• Sally’s daughter, Claire, has been diag nosed with a rare, autosomal recessive condition called Random syndrome. Sally and Claire’s father are divorced. Sally and her new husband, Bernard, have just learned they are pregnant and are worried about the risk that their baby will also have Random syndrome.

  

• You know that that incidence of random syndrome is 1/14,400 but a

  carrier frequency has not been reported.

  Provide Sally and Bernard with a recurrence risk estimate for their baby.

• To calculate the risk to a pregnancy for an autosomal recessive disease you multiply

  the chance that each parent is a carrier by the ¼ chance that two carrier parents would both pass on the mutation (which is always ¼).

  • We know that Sally has to be a carrier

  • The incidence rate in the population is 1/14,400

  • 1×bernards chance of being a carrier×1/4

• Practical hardy-weinberg

  • The carrier frequency of an autosomal recessive disease in the general population can be determined from the disease incidence

    

  • So Bernards chance to be a carrier =2pq

    

  • Since p+q=1, and q is so small, we can assume that p=1

    

• Probability that the baby is a carrier = 1×1/60×1/4

  • 1 in 240

Ethnicity-based carrier screening

• Northern European Caucasian — cystic fibrosis

• French Canadian and Cajun — Tay Sachs disease

• Ashkenazi Jewish ancestry

  • Much of the US Jewish population

  • Evidence suggests that the Ashkenazi Jewish population bottlenecked and experienced founders effect

• Dor Yeshorim

  • International genetic screening system

  • Adults submit a blood sample tested for common autosomal recessive diseases

  • each participant receives an identification number but does not get the results

  • When two people are considering an engagement or when a rabbi is attempting to arrange a marriage, the identification numbers can be submitted to determine if the couple is compatible (not carriers for the same condition)

• Pan-ethnic carrier screening

  • Screening for many different genetic conditions regardless of ethnic background

2/4/2025

Birth Defects

• Birth defect = congenital anomalies

  • It can be major or minor

• 3-5% incidence rate

• Causees

  • Sporadic: usually isolated within a family, unknown etiology, not expected to be inherited

  • Chromosomal syndromes

  • Genetic syndromes

  • Teratogens

  • Positional

• Vocab

  • Isolated: not associated with other anomalies, etiology might be known, may be inherited

  • Syndrome: a well-known pattern of anomalies believed to have the same cause, often genetic/chromosomal but may be environmental

  • Sequence: a group of related anomalies believed to be caused by a single major anomaly that alters the development of other structures

Common major anomalies

• Heart defects

  • 1/200

  • Usually sporadic

• Neural tube defects (spina bifida)

  • 1/1000-1/200

  • Usually sporadic

  • May be environmental

• Club food

  • 1/1000-1/500

  • May be positional

• Pyloric stenosis

  • 1/500 males, 1/1000 females

• Clef lip

  • 1/1000-1/500

  • Usually sporadic by also associated with many genetic and environmental syndromes

• Gastroschisis

  • 1/10000

  • Usually sporadic, may be related to maternal age or smoking

Common minor anomalies

• 2,3-toe syndactyly

• Occular anomalies

  • Hypoterlorism/hypertelorism (eyes being close together or far apart

Syndrome vs sequence

• Syndrome: Achondroplasia

  • Dwarfism

  • Comes with short limbs, frontal bossing, low nasal bridge

  • FGFR3 gene mutation

• Sequence: Oligohydramnios sequence

  • Potters sequence

  • Limited lung development, joint conttractures

  • Low amniotic fluid causing fetal compression

  • Symptoms are all the result of one abnormality

Heirarchy!

Organelles

• Peroxisomes

  • Participate in energy metabolism

  • Replicate independently of the cell but do not have their own genome

  • Break down uric acid and other waste products

  • Lipid biosynthesis

  • Cause Zellweger syndrome

    • Autosomal recessive

    • 12 peroxin genes (locus, allelic, and clinical heterogeneity)

    • Low muscle tone, dysmorphic features, seizures, lover disease, usually die within the first year of life

Cellular structure

• Demyelinating diseases

  • Loss of the myelin sheath

  • Neurologic deficits due to failure to transmit signals across the neuron

  • Can be reversible

  • Causes:

    • B12 deficiency

    • Tay Sachs disease

    • Biral infection

    • MS

    • Alcholol

Skin Cells

• Epidermis, dermis, and hypodermis

• Protects against environment

• Sensory

• Fat storage

• Vitamin production

• Epidermolusis bullosa

  • Extreme skin fragility with blistering

  • Healing around the digits may lead to fusion of the fingers and toes

  • Mucosal tissues may also be involved

  • Teeth and nails fall out

embryology

• The zygote in each cell in very early stage vertebrate embryos can give rise to every type of adult cell

  • Stem cells

• 

• Fetal alcohol syndrome

  • Effect dependent upon exposure amount an timing

  • Changes to facial features

  • Intellectual disability

Case study

• Melody and Kevin have just given birth to their second child, a

  daughter named Fern. The family has recently moved

  to the area and Melody’s prenatal records have not yet been

  transferred. The couple shares with you that they were told that

  their baby would have cleft lip and palate and might have other

  concerns as well. You have been asked to evaluate the baby

  • MRI shows semi lobar holoprosencephaly

    

  • Holoprosencephaly

    • Abnormal development of the forebrain leading to incomplete separation of th cerebral hemispheres

2/5/2024

Genetic variation

• Genetic variation is measured at 2 levels

  • Within a population (among individuals)

    • Consider population history/current size

    • Big populations tend to have more diversity

    • Populations that have gone through a bottleneck tend to have less diversity

  • Among populations (of the same species)

    • Consider gene flow/connectivity

Types of genetic variation

• Chromosomal

  • Karyotypes describe what your chromosomes look like

  • Sex chromosomes vs autosomes

  • Haploid = n

  • Diploid = 2n

  • heterogametic = different sex chromosomes (XY)

  • homogametic = same sex chromosomes (XX)

  • Variation in chromosome number can be problematic for inter-breeding

    • horses: 2n=64, n=30

    • donkeys: 2n=62, n=31

    • mule: 2n=63, no n — infertile

      • one chromosome can’t pair up in meiosis

    • But things get weird! sometimes hybrids with odd numbers of chromosomes can reproduce

  • Chromosome variation is problematic during meiosis

    • Genetic information does not align during crossing over; interferes with gamete production

  • Chromosomes can fuse together, so you can have species within the same genus with very similar DNA sequences but different numbers of chromosomes

  • Polyploidy: Have different numbers of sets of chromosomes

  • Chromosomal rearrangements

    • Inversions

      • Chromosomal inversion separates annual and perennial ecotypes of monkey flower

      • Adaptive differentiation

    • Translocations

• Mitochondrial DNA

  • Useful for phylogenetic questions

  • Only maternally inherited

    • Eggs are big, sperm are small

    • There are many more mitochondria in the egg

  • It doesn’t vary much between individuals of the same family

    • Can be useful for separating groups

    • Whole genome acts as one locus

  • You can use mitochondrial DNA as a marker when you can’t with nuclear DNA bc you will always have more copies of the mitochondrial DNA

  • Used to look at differences between Ridley Sea Turtles across the world

  • Can also be used to look at differences among species (phylogenetic perspective)

• Chloroplast DNA

  • Useful for phylogenetic questions

  • Only maternally inherited

  • Chloroplast DNA variation resolved species relationships in the carrot/parsley family

  • Assaying variation in mitochondrial or chloroplast DNA

    • Sequence a gene region or the whole mitogenome (DNA sequencing)

    • Restriction enzyme analysis of a known polymorphism (genetic marker)

• Nuclear DNA

  • Biparental inheritance

  • Assay for nuclear DNA variation

    • DNA sequencing (whole genome sequencing)

    • Genetic marker approaches

      • Microsattelites:

        • Highly variable due to high mutation rate

        • Multiallelic

        • Typically neutral (not under selection)

        • Alleles differ by length of sequence

          • Made up of sequences of repeated blocks of DNA

• Genetic markers - microsatellites and SNPs

  • SNPs: Single Nucleotide Polymorphisms

    • Arise from point mutations

    • Bi-allelic

    • Abundant in the genome (millions)

    • Easily identifiable with modern genomic methods

2/6/2025

Twinning

• Monozygotic (identical) twins

  • Arise from one fertilized egg which splits into two embryos

  • Genetically identical at conception

  • Always same sex

  • Complications

    • Monochorionic diamniotic: twins that share a placenta but are in different amniotic sacs

      • Twin-to-twin transfusion system: Flow of blood from one twin to another causing severe stress on both babies systems

    • Monochorionic-monoamniotic: twins that share a placenta and are in the same amniotic sac

      • Can lead to cord entanglement or conjoined twins

    • Discordance for a genetic condition: de novo mutations can happen after the embryo splits, leading to one twin with a genetic disorder

• Dizygotic (fraternal) twins

  • Arise when two eggs are ovulated and fertilized

  • Genetic full siblings

2/13/2025

Cancer

• All cancers are genetic BUT cancer is very rarely inherited

• only 5-10 percent of all caners are caused by inherited mutations

• Mutations arise in somatic cells

Six features of cancer cells

1. Independence of external growth signals

2. Insensitivity to external anti-growth signals

3. Ability to avoid apoptosis and autophagy

4. Ability to replicate indefinitely

5. Ability of a mass of such cells to trigger angiogenesis and vascularize

6. Ability to invade tissues and establish secondary tumors

Important concepts

• We have several protective systems

  • Repair

  • Apoptosis

  • Immune response

• We need several mutations to convert normal cell to tumor cells

• Low probability except

  • Some mutations enhance cell division

  • Some mutations affect genome stability

  • Some mutations reduce immune response

Cancer mutations

• Multi-stage evolutionary process

• You need something to select for cancer expansion, or something that stops you from getting rid of the cancer cell

• Cell cycle dysregulation is the cardinal feature of cancer cells

  • In G1, RBP1 TP53 and CDKN2 play key roles

  • Associated with somatic and familial changes in tumor cells

Genes that result in acquired cancer cell

• Oncogenes — “gas pedal”

  • When they are normal, they promote cell proliferation

  • Gain of function mutations result in forms that are too active

    • 

    • Point mutations decrease activity increasing signal in pathway

      • GTP-RAS, MAP kinase pathway is on all the time

    • Rearrangements can activate oncogenes

      • Philadelphia chromosome: A balanced translocation 9;22 found in 90% of people with chronic myeloid leukemia — BCR-ABL1 chimeric tyrosine kinase fusion protein is always active.

      • In Burkitt lymphoma 8;14 translocation places MYc in transcriptionally active region - -MYC is upregulated under the influence of the normally highly expressed immunoglobulin genes IGH expresss

  • Discovered as part of retroviruses capable of transforming cells

    • Reverse transcribe DNA — form of duplication

    • Oncogenes turned out to be copies of normal cellular genes (proto-oncogenes).

    • 15% of cancers are caused by retroviral infection

• Tumor suppressor genes — “brake”

  • Normal activity limits cell proliferation, likks incorrigible cells, and maintains genome intgrity

  • loss-of-function mutations lose ability to control cell proliferation

    

  • Retinoblastoma is the paradigmatic TS gene and the two-hit hypothesis

    • You get a tumor when you get a second mutation

    • Inherited or sporadic mutation

    • Recessive but behaves like it’s dominant due to two hit hypothesis

      • Recessive at the cell level, dominant at the retina level

      • If you inherit the bad allele, you will get the sporadic mutation as well

        

    • Rb1 binds and inactivates E2F stopping progression into S phase

Mechanisms for loss of wildtype allele in RB

• Top of diagram is heritable heterozygous state. 2 markers flank the gene

  • A1 and A2 and B1 and B2 are different sizes

• N=normal. T=tumor

• Non-disjunction:

  • One chromosome with the RB gene, other chromosome is absent

  • Doesn’t have to be a mutation — this cell is homozygous for RB

• Non-disjunction+ duplication

  • Same as ^ Mutated chromosome is duplicated

• Mitotic recombination

  • Chromosome 2 has recombined and grabbed the part of chromosome 1 with RB

• Deletion: delete the part of the wild type chromosome with the allele

• Second mutation:

• Inactivation by methylation

LOH

• LOH= loss of heterozygosity

• Used as a marker to locate tumor suppressor genes

2/18/2025

Cancer facts

• 77% occurs in people over 55

• 5 year survival rate is 67%

Cervical cancer

• 12,000 women per year

• Caused by HPV

  • Strains 16 and 18 most likely to cause cervical cancer

  • Most common sexually transmitted virus in the US

• Virus invades epithelial cells, DNA is integrated into genomes

  

  • P53 is a tumor suppressor gene

• Prevention

  • Don’t have sex

  • Cervical cancer vaccine

The philidalpihia chromosome

• Chromosomal translocation that generates a kinase involved in the signal transduction cascade that is always on

• t(9;22)(q34;q11)

• Involved in leukemia

• Somatic (not germline) event

  • Cannot be inherited

• 3 clinically important isoforms associated with different cancer types

  • Acute lymphoblastic leukemia (ALL)

  • Chronic myeloid leukemia (CML)

  • Chronic neutrophilic leukemia (CNL)

• BCR-Abl fusion protein

  • Tyrosine kinase always on

  • Increased speed of cell division

  • Inhibits DNA repair (causing genomic instability)

• Cleevec

  • Treatment for the Philadelphia chromosome

  • Tyrosine kinase inhibitor — targets BCR-Abl protein

  • Doesn’t affect other tyrosine kinases

  • Only effective in Ph-positive CML

Inherited cancers

• 5-10% of cancer is inherited

• Young age of onset

• Organs affected bilaterally

• Multiple family members affected

• Multiple primary cancers

• Primary cancer: Arose as the result of a new event in the affected tissue

• Recurrent/Secondary cancer: The result of the incomplete eradication or metastatic of another cancer

Retinoblastoma

• Unilateral cases have an average onset of 24 months

• Bilateral cases have an average onset of 15 months

• Inherited retinoblastoma

  • RB1 gene

    • Tumor suppressor gene

    • Up to 8% will have a deletion that could also cause intellectual disability and birth defects

  • Autosomal dominant at the level of the organism, autosomal recessive at the level of the cell

  • 95% survival rate with treatment

  • Other cancers can also be associated

Breast/ovarian cancer

• Women have a 12% risk of breast cancer, 1.4% ovarian

• Inherited breast-ovarian cancer incidence: 1/800-1/2500

• 5-10% are caused by germline mutations (inherited) in BRACA1 and BRACA2

  

• BRCA

  • Expressed across many cell types

  • Mutations cause loss of gene function —> tomorrow suppressor genes

  • Suspected involvement in DNA repair

• Management

  • Climical breast exam

  • Mammography

  • Breast MRI

  • Ultrasound (ovarian)

  • Blood test (ovarian)

Colorectal cancer

• 5% risl

• Up to 33%B of colorectal cancers are caused by germline mutation but only 3% are highly penetrant

• Lynch syndrome: Caused by germline mismatch repair gene mutations

  • Immunohistochemistry (ICH): Tissue staining procedure, detects the presence or absence of proteins produced by mismatch repair genes

  • Microsatellite instability testing (MSI): Evaluation for instability in the size of microsatellite markers. More accurate than IHC

    

Li-Fraumeni syndrome

• “huntingtons disease of cancer”

• Incidence as high as 1/5000

• Caused by TP53 tumor suppressor gene

• Cuases many different cancer types

• 50% of affected individuals will have cancer diagnosed before 30 years old

Multiple endocrine neoplasia

• MEN1: Wermer’s syndrome

• MEN2A: Sipple syndrome

  • Incidence 1 in 35000

  • Autosomal dominant

  • RET gene, 10q11.2

    • Protooncogene

    • Regulates cellular environmental responses, promotes growth and division

    • Mutations over-activate the gene (tyrosine kinase is always active)

    • RET gene mutations also cause Hirschprung disease

• MEN2B:

Liquid biopsy

• Used to test fetal genome from mother’s blood

• Used for tumor diagnosis — tumors have genomic instability

2/25/2025 Analyzing genomes using technologies

testing

• Diagnostic testing: confirms or rules out specific genetic condition

• Predictive and pre-symptomatic testing: used to detect mutations associated with disorders that appear after birth but before symptoms (ex: BRCA)

• Carrier testing: used to identify individuals who carry one copy of a recessive condition

• Preimplantation genetic diagnosis (PGD): used in in vitro fertilization to identify embryos without genetic abnormalities for implantation and pregnancy

• Prenatal testing: Used to detect changes in a fetus’s genes or chromosomes before birth (amniocentesis or chorionic villus sampling)

• Newborn screening: Testing newborns for disorders (PKU or phenylketonuria)

Testing methods

• PCR: makes millions of copies of a target DNA sequence from very small sample and is the base technique for most genetic testing

  • Key techniques in most genetic tests

  • YOU WILL BE ASKED TO DESIGN A PCR EXPERIMENT ON THE EXAM

    

  • Directions are important (replication goes in 5’ to 3’ direction)

  • New bases get added to 3’OH

• Next generation DNA sequence: Sequencing of an individuals entire genome

• Microarrays (DNA chip technology: Analyze gene expression and detect SNPs. Basis of 23 and me

• Karyotyping: Visual examination of chromosome number and structure

• FISH: uses fluorescent probes to target specific sequences to assay for specific sequence

• Biochemical genetic testing: examines the amount or activity level of proteins that can indicate abnormalities

  

Types of variation

• SNPs

• Deletions and duplications

  • Indel: deletion and duplication <1000 bases

  • CNV: deletion and duplication >1000 bases

• Trinucleotide repeat expansion (TNR): increased number of trinucleotide repeats in a given area of a gene (Friedeich ataxia, Huntington

• Methylation: Addition of methyl groups to DNA can turn the gene off

• Mitochondrial DNA variants (MtDNA). Changes to the DNA in the mitochondria

Clinical genet tests

• Single gene testing: Single gene testing is done when there are symptoms of a

  specific condition or syndrome. (i.e. Duchene muscular dystrophy or sickle cell

  disease) or when there is a known genetic mutation in a family.

• Panel testing: Looks for changes in many genes in one test and are usually

  grouped in categories based on different kinds of medical concerns (i.e. low

  muscle tone, short stature, or epilepsy or risk of developing breast or colorectal

  (colon) cancer

• Large-scale genetic or genomic testing. There are two different kinds of large-

  scale genetic tests.

  • Microarrays and SNP arrays looks for INDELs and predetermined SNP

  • Whole Exome sequencing looks at all the expressed parts of genes in the DNA.

  • Whole Genome sequencing looks at all of a person’s DNA, not just the genes.

Large scale genotyping in humans

• Screening

  • DNA microarrays

  • Focused genome sequencing

    • SNP chips

    • PCR amplification

    • Hybridization capture

  • WGS

• Sxperimenting

  • Transcription profiling

    • RNA arrays, RNA seq, qPCR, ddPCR

  • Epigenetic analysis

  • Protein DNA interactions (ChIP-seq)

Human genetic variation

• Chromosome variation: typically limited to larger deletions, duplication. and translocations 5Ml>

• Segmental values (copied number variation): 1kb-5kb

  • Most but not all are associated with segmental duplications

  • Responsible for most differences (per base tail) between humans

• Single nucleotide polymorphisms (SNPs)

  • Base substitutions and small Indels

• COULD BE ON EXAM

• 

Microsatellites (SSRs)

• Several short repeated motifs

• Highly polymorphic

  • Good genetic marker

  • Good forensic tool

• Sometimes directly related to disease

  • Huntingtinon’s and fragile x

• Assay by PCR and length analysis

• Not all trinucleotides

  

  • Different lengths=different alleles

PCR

• How do we identify and detect a specific gene sequence in a genome?

• 2 big issues

  • There are a lot of other sequences in a genome that we’re not interested in detecting (specificity)

    • 1/4ⁿ is the probability of finding a sequence at random

  • The amount of DNA in samples we’re interested in is very small (amplification). Contamination is very dramatic

• Type of question that will be on the midterm

  

  • Mark the orientation of the forward and reverse primer

2/28/2025

• exam question: match red and blue lines with the PCR

Testing

• Microarrays are useful for detecting DNA deletions and duplications

Sequencing

• Traditional DNA sequencing/chain termination quequencing/sanger sequencing

  

  • Separate strands of different lengths by gel electrophoresis

  • Used dideoxyribonucleic acid — H on the 3’ carbon means it won’t bond with anything else

• Next generation DNA sequencing technologies

  • Much cheaper — don’t have to run gels

  • It is still expensive to analyze the genome

• Sequencing by Synthesis (Illumina)

  • Second generation sequencing

  • Goal is to monitor replication

    

  • P5 and P7 (red and green) are primers sites

  • Sequence on the inside surface of a flowcell

  • Primers are covalently attached to the glass

    

    

  • Needs to be amplified with PCR as well’

  • Bridge PCR

    

    • Just like normal PCR except primers are stuck to the glass

    • End up with clusters of identical DNA molecules

    

  • Need to get rid of color

    

  • Illumina stargazing

    

• PacBio

  • A bunch of wells in a plate

  • At the bottom of the wells there is a hole

  • Holes are such a size that we can look in but nothing will come out

  • Incorporating fluorescent nucleotides

  • Single molecule real time sequencing (SMRT)

    

• Nanopore sequencing

  • You have a protein hat unzips the DNA and pumps the sing strand through a pore in a membrane

  • Measure change in electrical activity across the membrane at every pore

  • Electrical activity changes for each nucleotide

  • Really long reads

  • MinION field sequencer

KNOW THE 4 SEQUENCING TECHNOLOGIES

Array based genotyping

• Arrays contain oligonucleotides that test the seuqnce of a sample

• Arrays target the test to a set of loci

• They function based on the discrimination of complementary base pairing or the ability to extend a base at a specific location

• Transcription profiling

  • Arrays can be used to measure the amount of RNA produced by a set of genes

  • Sequencing can be used to measure expression of a genome

Epigenetics

• Methylation — histones influence what portions of the genome are available for transcription

• bisulphite sequencing

  

  • If the C is not methylated, it switches it to be a U

  • Everywhere C that is remaining you know is methylated, so you can map these points

ChiP-seq

• Used to study protein DNA interactions

3/4/2025

Standard of care

• Standard of care: that which a minimally competent physician in the same field would do under similar circumstances.

• Not intended to replace the good judgement of clinicians

Cell free fetal DNA testing

• Can be used to detect gender as early as 8 weeks

  • Female is more susceptible to error

• Takes blood sample from mom

Karyotyping vs array

• Both detect aneuploidy and segmental variation

• Microarray can detect much smaller CNVs than karyotype

• Karyotype can detect balanced translocations (microarray can’t)

Case 1

• You are as ked to evaluate Sally, 2 years old, for a history of Tetralogy of Fallot, clubfoot (bilateral), failure to thrive, and recurrent infections. She is otherwise healthy and has shown normal development. Her parents report the following family history.

• Teralogy of fallot

  • Heart defect

  • Strongly associated with 22q11.2

  • 6% of isolated cases of ToF have 22q11.2 deletions

• 22q.11.2 deletion syndrome: digeorge syndrome

  • Incidence 1/4000

  • Can test using karyotyping or FISH or microarray, but microarray is standard of care

    

• For sally, the microarray identifies a 22q11.2 deletion

  

  • Next step is to offer testing for other family members via FISH

Case 2

• Betty is 19 weeks pregnant and has been referred to your practice. Her obstetrician is concerned because a recent ultrasound showed very small nasal bone, small cerebellum, choroid plexus cyst, and a single umbilical artery. Your ultrasound confirms the fetal findings. Betty and her husband, Luke, report that there is no significant family history

  • Small nasal mone — Down

  • Choroid plexus cyst — Trusomy 18

  • Single umbilical artery — could be anything

• Options

  

  • Microarray is best option

• A 5p15.2-p15.33 deletion is detected: Cri-du-chat (cat cr y) syndrome

  • 1/20000 -1/50000 incidence

  • Newborns make cat like cry

  • Microcephaly

  • Severe intellectual and motor disabilities

  • Dysmorphic facial features

• Next step: find a critical region

  • We know this is a spontaneous event

    

    • Look at where deletions actually span. Places critical region for cat-like cry phenotype in the 15.2 area

Case 3

• Edward is a 7 year old boy with a history of microcephaly, atrial septal defect, long palpebral fissures, large ears, polydactyly, intellectual disability, elevated liver enzymes, mild anemia, and several food allergies including eggs and

  wheat. He has already had an extensive genetic work -up which as been normal thus far. You are seeing Edward and his mother, Rhonda, for follow-up

• Tests already done

  • Karyotype: 46,XY

  • Fragile X syndrome: normal

  • MECP2 analysis (atypical Rett syndrome): normal

  • L1CAM analysis (X-linked hydrocephalus): normal

  • Williams syndrome: normal

  • Mitochondrial function studies : normal

  • Microarray: normal

• Options

  

  • Whole exome sequencing is the best option here

The Rominovs

• Determining who was in the mass grave

• Focused on mitochondrial DNA

  • We understand it’s the inheritance patterns

  • Evolves rapidly

• Mitochondrial DNA testing showed that Prince Philip shared a common female ancestor with Alexandra and three of her daughters from the first grave

  • Also showed that Duke of Fife and Princess Xenia shared a common female

    ancestor with Nicholas.

  • Nicholas’ remains showed a single point heteroplasmy in the mtDNA (16169 C/T) that was not seen in his maternal relatives (16169 T). This rare

    heteroplasmy was shared by his brother, Grand Duke Georgij Romanov.

• But

  • The remains of only 3 children were discovered in the first grace, Alexei and one sister were missing

  • Found the second grave in 2007

• The second grave

  • Forensic anthropological analysis

    • The second grave contained two people

    • 15-19 year old female

    • 12-15 year old male

    • Ethnicity and height could not be determined for either victim

    • Silver fillings showed that at least one victim was an aristocrat

    • The grave was over 60 years old

  • DNA analysis

    • DNA was extracted from several bone sites (mostly long bones)

    • PCR was used to amplify and quantify (real-time PCR - qPCR) the

      extracted DNA

    • Multipex PCR was used to used to amplify and sequence the mt DNA

    • DNA from the Y chromosome was also amplified using PCR

  • Samples from the second grave matched the mtDNA studies from the first grave and from prince Philip

  • Genotyping results

    

    • Markers are microsatellites

    • Found using PCR — design primers to look for specific primers

  • Y-linked marker results

    

  • Conclusions

    • All of the Ramonov family were murdered on July 17, 1918 and buried in two separate mass graves

DNA forensics

• CODIS

  • CODIS: Combined DNA Index System

  • Operated by the FBI

  • Contains DNA profiles from convicted offenders and arrestees in states where collecting this data is legal

  • Contains DNA profiles found at crime scenes

  • Only works if everyone decides to use the same markers!!

• Process

  • Law enforcement agencies submit DNA profiles derived from samples

    taken as part of a criminal investigation

  • Sample DNA profile is compared to the CODIS database

  • If a match is found in the Convicted Of fender/Arrestee database, it is usually possible to obtain a warrant to collect a sample from the matched an individual for a reference sample

  • If a match is found in the Forensic Index the crime can be linked to

    one or more other crimes

• Accepted DNA profiles

  • STR (short tandem repeats): 20 loci

  • Y chromosome STR

  • Mitochondrial DNA (mtDNA)

  • Second 2 only ised to identify missing persons

• GEDmatch

  • Online tool

  • Users submit their raw DNA for analysis and comparisons with other users

  • Has been used by law enforcement to identify suspects and missing persons

  • Has a lot of data from both ancestry and 23andme

  • Open to everyone

The Golden State Killer

• Joseph James DeAngelo murdered at least 12 people

• Cold case for 44 years

• Arrested in 2016 at age 72

• No match for DNA sample in CODIS

• Comparison of DNA taken from a crime scene was submitted to GEDmatch and several partial matches were made

• Degree of relationship to the sample DNA was inferred from the amount of similarity between the sequences — people who he was related to

• This provided a narrower field of suspects
  

Brave new world

• Analysis of a DNA sample taken from a crime scene can be used to infer ethnicity and physical characteristics

• Modeling software was used to show the effects of age

Paternity testing

• Analysis of 10-20 markers

3/6/2025

Exam info

• modules 4 5 and 6

New genes come from gene duplication

• Mechanisms of gene duplication

  • Tandem gene duplication (direct or inverted) unequal crossing over (homologous chromosomes) or unequal sister chromatid exchange (same chromosome)

  • Duplicative transposition (typically retrotransposition)

  • Ancestral cell fusion (think endosymbiont theory)

  • Large-scale, sub genomic duplication (segmental duplication inter and intra chromosomal)

  • Whole genome duplication

• Protein coding genes beget protein coding genes

  

  • Involved in oxygen transfer

• We use phylogenetic trees to understand how genes evolve

  • Globins diverged in evolution

• Usually when there is a gene duplication, one becomes nonfunctional

  • Neofunctionalization is the process by which a gene acquires a new function after a gene duplication event.

    

  • Subfunctionalization is a neutral mutation process in which each paralog retains a subset of its original ancestral function

    

    • The part upstream of the gene

• Pseudogenes: genes that have been copied and are now not functional

  

  • Mutation in the stop codon or other critical region

  • In B, these are generated from reverse transcribed mRNA

    • Processed pseudogenes

    • You can tell if it’s processed by whether it has exons — if it’s processed, it will have already been spliced

  • Gene to make our own vitamin C is a pseudogene

    • Limited to primates and bats

    • This is why we need dietary vitamin C

Whole genome duplications

• How do we know these are whole genome duplications and not individual gene duplications

  • Genes that are similar to each other interact — form gene families

    

• X chromosome is completely conserved

  • Due to Barr bodies — silencing one x chromosomes

  • X genes on mice are probably in X genes in humans

Functional diversity of DNA in humans

• There are RNAs that control gene function and regulating transcription/translation

• There are probably 2x as many genes coding for RNAs as proteins

genome organization

• Transposons

  • Transposon repeats make up 40% of your genome

    

    • There are a lot of diseases associated with LINE-1 family elements

      

    • Alu family was one of the biggest barriers to sequencing the genome

    • Why do we have so many? A few ideas:

      • these are parasites — they care about their own replication and are successful because they can move around the genome and duplicate

      • DNA methylation evolved to silence these transposons

      • These are advantageous because they are a source of variation

Model organisms

• Used to understand facts of biology and evaluate potential therapies

• Comparing genome sequences provides genome-wide information on relatedness of DNA and protein sequences

• Used to infer function by orthology

  • harder with more evolutionary difference

• What makes a good model?

  • Easy to grow

  • Easy to manipulate

  • Not sympathetic

  • Closely related to humans

• Assigning function to human genes

  • We cant experiment on humans

  • Model organisms are great for experiment advancing our understanding how a protein functions

  • We can identify the same protein in human genomes and assign the function determined in the model

  • 50% of human gene functions come from yeast

• Dogs are good for understanding genes that code for morphological and behavioral differences between breeds

  • Chondrodysplasia: a collection of diseases that can affect a person's stature

  • Studied in dogs

  • All small breeds have FGF4 retrogene on CFA12

Genes across species

• Odine’s curse: congenital central hypoventilation syndrome

  • Affects the autonomic nervous system

  • Hypoventilation — children with this disease need a thrach to survive

  • Hirschprung disease

  • Caused by a mutation in the PHOX2B gene (4p12), only gene associated with it

  • Autosomal dominant

  • Homeobox gene family

    • Made up of 235 genes and 65 pseudogenes

    • transcription factors

      • Homeodomain: DNA binding region (helix-turn-helix)

    • Expression of these genes during development follows same patterns in model organisms

    • Can also lead to mixed up limbs and in model organisms

    • In people, they can impact development of digits

• Extra SMNs — case study

  

  • SMA

    • SMN1 gene, 5q13.2

    • 95-98% are homozygous for a deletion or truncation of exon 7

    • 62% of SMN1 genes are composed of repetitive elements

    • Autosomal recessive

    • Degeneration of motor neurons

  • 

• Evolution of the SMN gene

  • Mice and rats only have one SMN gene → the inverted duplication arose after humans diverged from mice

Sickle cell anemia

• 20A→ T mutation HBB gene — 11p15.4

• Autosomal recessive

• Sickled cells clog small blood vessels

• important in malaria resistance

betal globin gene family

Alpha globin gene family

Apert syndrome

• Apert syndrome is caused by mutations in FGFR2 gene

• Craniosyntosis, midface hypoplasia, syndactyly of hands and feet, fusion of cervical vertebrae

• There are 7 other syndromes caused by the same mutations

• Most mutations are missence mutations

• FGFR2 shows alternative splicing. A known Alu insert in exon IIIc inappropriately promotes splicing to form FGFR2

Lil bub

• 

• homozygous deletion of exon 8 of the TNFRSF11A gene

• Encodes RANK protein