18.01.22 Origin of UPD Flashcards
What is UPD and how frequent is it?
Two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent.
Frequency ~1 in 3,500 (Robinson et al., 2000). Orphanet definition of a rare disease is 1 in ≥2000.
When do abnormalities arise from UPD?
UPD for some chromosomes does not exert any adverse effect on an individual
Abnormalities arise when:
1) Genes within the UPD region are subject to genomic imprinting
2) Homozygosity for recessive mutations: two copies of a recessive mutation from a parental carrier
3) UPD resulting from a somatic mutation can cause LOH or LOI (loss of imprinting)
4) UPD in conjunction with mosaicism for a chromosomally abnormal cell line e.g. placental or sometimes foetal mosaicism due to trisomy rescue
What is genomic imprinting, what effect on these genes can be caused by UPD?
Differential expression dependent on parent of origin
Leads to monoallelic expression of either the maternal and paternal allele of a diploid locus (‘parent of origin effect’)
UPD for an imprinted region results in two active, expressed parental alleles or two silent, repressed parental alleles, depending on the contributing parent
UPD results in abnormal dosage of the imprinted gene products
Give examples of how UPD resulting from a somatic recombination can cause loss of heterozygosity (LOH) or loss of imprinting
Somatically acquired UPD (aUPD) in cancer e.g. retinoblastoma, Wilms tumour.
Pre-existing driver mutation is converted to homozygosity, providing an additional clonal advantage
Somatic recombination leading to mosaic segmental UPD is probably common to all individuals and is more likely to occur with increasing cell divisions. Results in late onset conditions [Robinson 2000].
Give examples of three conditions associated with UPD
- [upd(6)pat] - transient neonatal diabetes
2, [upd(7)mat] - Russell-Silver syndrome
- [upd(11p15.5)pat] - Beckwith-Wiedemann syndrome
- [upd(14)mat] - short stature and precocious puberty with mild delay
- [upd(14)pat] - distinct skeletal dysplasia with asphyxiating thorax
- [upd(15)mat] - Prader-Willi syndrome
- [upd(15)pat] - Angelman syndrome
What are the two different forms of UPD?
- Uniparental isodisomy (UPID): The presence of two identical copies of one parental homologue. (Likely Meiosis II nondisjunction or mitotic error)
- Uniparental heterodisomy (UPHD): The presence of both homologues from the transmitting parent. (Likely Meiosis I nondisjunction).
Why might UPD along the length of an involved chromosome pair can be UPID for certain loci and UPHD for others?
Recombination in meiosis I e.g. in the distal long arm, followed by meiosis I non- disjunction could lead to a disomic gamete isodisomic for the distal long arm and heterodisomic for the proximal long arm. Or vice versa if the nondisjunction was in meiosis II.
Don’t confuse this with segmental UPD, which is UPD for only part of the chromosome and occurs by recombination during mitosis rather than meiosis.
What are the three categories of UPD?
- UPD for the entire chromosome complement
- UPD for a complete chromosome.
- UPD for a Segmental UPD (11% of all known UPD cases)
Give examples of disease associated with UPD of the entire chromosome complement.
- Complete hydatidiform mole: UPD for the entire diploid complement, exclusively paternal in origin (UPDpat). Predominantly 46,XX karyotype due to endoreduplication of a single 23,X sperm [Gardner and Sutherland].
- Benign cystic ovarian teratoma: Maternal UPD (UPDmat) for the entire diploid complement. Arises in a germ cell due to failure of a premeiotic or meiotic cell division [Gardner and Sutherland].
- Triploidy (partial hydatidiform mole): Extra set of chromosomes can have either a maternal origin (digynic triploidy) or paternal origin (diandric triploidy) [Devriendt 2005], usually paternal [Gardner and Sutherland].
Can get mosaic UPD/triploidy [Liehr 2014].
Mosaicism for UPD of the entire diploid complement (maternal or paternal) with a biparentally-inherited karyotype is a rare finding in living newborns.
Mosaicism for UPD of the entire diploid complement (maternal or paternal) with a biparentally-inherited karyotype is a rare finding in living newborns, resulting from one in three mechanisms, describe these.
Major mechanisms of formation of genome wide uniparental disomy (UPD) mosaicism:
(A) fertilisation of an egg by one sperm, and irregular reduplication and division of the male pronucleus followed by cell division and diploidisation of the male haploid genome resulting in a cell line with a normal biparentally inherited karyotype and a genome wide uniparental cell line;
(B) fertilisation of an egg by two sperms followed by cell division and diploidisation of the haploid male genome; or
(C) fertilisation of an empty egg and subsequent diploidisation of the male haplotype as well as of a normal egg with a haploid chromosomal complement by a normal sperm followed by amalgamation of both.
How can UPD for a complete chromosome arise?
1) Trisomy rescue (most common)
2) Gamete complementation (very rare)
3) Monosomy rescue
4) Mitotic error
Describe trisomy rescue.
Meiotic nondisjunction in one parent results in a disomic gamete.
Fertilisation of this disomic gamete with a normal haploid gamete results in a trisomic conceptus.
‘Rescue’ through loss of one homologue (perhaps through anaphase lag) at a very early postzygotic stage (possibly even in the zygote), results in UPD in 1/3 cases.
What is the result of trisomy rescue at meiosis I and meiosis II.
Meiosis I nondisjunction uniparental heterodisomy (UPHD)
Meiosis II nondisjunction uniparental isodisomy (UPID)
Because the loss occurs postzygotically, mosacism in such conceptuses is often observed, with the trisomic cell line often confined to the placenta. Not uncommon to observe 100% trisomy in placental tissues with complete absence of trisomy in the fetal tissue [Robinson 2000]. UPD phenotypes may therefore be complicated by the effects of compromised placental function and/or fetal trisomy mosaicism.
What is the proposed reason why the conversion of trisomic tissue to disomy is rare during embryogenesis?
it may be that conditions present in the first few mitoses are conductive to correction, and this is soon lost post inner cell mass formation. i.e. occurs at a very early post-zygotic stage.
When do most non-disjunction events occur? What type of UPD does this result in?
Most aneuploidy results from maternal meiosis I nondisjuncton, therefore most UPDs arising from a trisomic rescue will be maternal heterodisomy.
What is the chance that carriers of a Robertsonian translocation that has arisen through trisomy rescue will have UPD?
50%
Describe gamete complementation.
Meiotic nondisjunction in both parents results in a disomic gamete from one parent and a nullisomic gamete for the same chromosome from the other parent.
A chance meeting of these gametes will result in a diploid zygote with UPD for that chromosome.
Although very unlikely that a meiotic error would happen coincidently in both parents, at least three cases have been recognised in the literature to result from this mechanism. In these cases, at least one parent carried a translocation for the chromosome involved [Shaffer 2003].
Hard to differentiate whether UPD has occurred by gamete complementation, or by trisomic rescue very early in development and no trace of the original trisomic cell.