X-linked recessive inheritance: Difference between revisions

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X-linked inheritance means that the gene causing the trait or the disorder is located on the X chromosome. Females have two X chromosomes while males have one X and one [[Y chromosome]]. Carrier females who have only one copy of the mutation do not usually express the phenotype, although differences in [[X-chromosome inactivation]] (known as [[skewed X-inactivation]]) can lead to varying degrees of clinical expression in carrier females, since some cells will express one X [[allele]] and some will express the other. The current estimate of sequenced X-linked genes is 499, and the total, including vaguely defined traits, is 983.<ref>{{cite web|url=https://www.ncbi.nlm.nih.gov/Omim/mimstats.html|title=OMIM X-linked Genes|website=nih.gov|accessdate=3 May 2018|url-status=live|archiveurl=https://web.archive.org/web/20160307090758/http://www.ncbi.nlm.nih.gov/Omim/mimstats.html|archivedate=7 March 2016}}</ref>

== Patterns of Inheritance ==

==Sex differences in phenotype/genotypes and frequency==

In humans, inheritance of X-linked recessive traits follows a unique pattern made up of three points. The first is that affected fathers cannot pass x-linked recessive traits to their sons because fathers give Y chromosomes to their sons. This means that males affected by an x-linked recessive disorder inherited the responsible X chromosome from their mothers. Second, x-linked recessive traits are more commonly expressed in males than females.<ref>{{Cite web|last=|first=|date=8 July 2009|title=Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals|url=https://www.ncbi.nlm.nih.gov/books/NBK115561/|url-status=live|archive-url=|archive-date=|access-date=9 June 2020|website=National Center for Biotechnology Information}}</ref> This is due to the fact that males only possess a single X chromosome, and thus only require one mutated X in order to be affected. Women posses two X chromosomes, and thus must receive two of the mutated recessive X chromosomes (one from each parent). A popular example showing this pattern of inheritance is that of the descendants of Queen Victoria and the blood disease hemophilia.<ref>{{Cite web|date=2014-03-04|title=History of Bleeding Disorders|url=https://www.hemophilia.org/Bleeding-Disorders/History-of-Bleeding-Disorders|access-date=2020-06-09|website=National Hemophilia Foundation|language=en}}</ref> The last pattern seen is that x-linked recessive traits tend to skip generations, meaning an affected grandfather will not have an affected son, but could have an affected grandson through his granddaughter.<ref>{{Cite book|last=Pierce|first=Benjamin A.|title=Genetics: A Conceptual Approach|publisher=Macmillan Learning|year=2020|isbn=978-1-319-29714-5|pages=154-155}}</ref> Explained further, all daughters of an affected man will obtain his mutated X, and will then be either carriers or affected themselves depending on the mother. The resulting sons will either have a 50% chance of being affected (mother is carrier), or 100% chance (mother is affected). It is because of these percentages that we see males more commonly affected than females.

In humans, generally men are affected and women are carriers for two reasons. The first is the simple statistical fact that if the X-chromosomes in a population carry a particular X-linked mutation at a frequency of 'f' (for example, 1%), then that will be the frequency that men are likely to express the mutation (since they have only one X), while women will express it at a frequency of f² (for example 1% * 1% = 0.01%) since they have two X's and hence two chances to get the normal allele. Thus, X-linked mutations tend to be rare in women.{{Citation needed|date=January 2020}}

== Push Back on Recessive/Dominant Terminology ==

The second reason for female rarity is that women who ''express'' the mutation must have two X chromosomes that carry the trait, and they necessarily got one from their father, who would have also expressed the trait because he only had one X chromosome in the first place. If the trait lowers the probability of fathering a child or causes the father to choose to only have children with women who aren't carriers (so as to create daughters who are carriers rather than expressers, and then only if no [[genetic screening]] is used), then women become even ''less'' likely to express the trait.<ref>{{Cite book|last=Pierce|first=Benjamin A.|title=Genetics: A Conceptual Approach|publisher=Macmillan Learning|year=2020|isbn=9781319216801|pages=154-155}}</ref>

A few scholars have suggested discontinuing the use of the terms ''dominant'' and ''recessive'' when referring to X-linked inheritance.<ref name=":0">{{cite journal|last1=Dobyns|first1=William B.|last2=Filauro|first2=Allison|last3=Tomson|first3=Brett N.|last4=Chan|first4=April S.|last5=Ho|first5=Allen W.|last6=Ting|first6=Nicholas T.|last7=Oosterwijk|first7=Jan C.|last8=Ober|first8=Carole|year=2004|title=Inheritance of most X-linked traits is not dominant or recessive, just X-linked|journal=American Journal of Medical Genetics|volume=129A|issue=2|pages=136|doi=10.1002/ajmg.a.30123|pmid=15316978}}</ref> The possession of two X chromosomes in females leads to dosage issues which are alleviated by [[X-inactivation]]. <ref>{{Cite journal|last=Shvetsova|first=Ekaterina|last2=Sofronova|first2=Alina|last3=Monajemi|first3=Ramin|last4=Gagalova|first4=Kristina|last5=Draisma|first5=Harmen H. M.|last6=White|first6=Stefan J.|last7=Santen|first7=Gijs W. E.|last8=Chuva de Sousa Lopes|first8=Susana M.|last9=Heijmans|first9=Bastiaan T.|last10=van Meurs|first10=Joyce|last11=Jansen|first11=Rick|date=2019-03|title=Skewed X-inactivation is common in the general female population|url=https://www.nature.com/articles/s41431-018-0291-3|journal=European Journal of Human Genetics|language=en|volume=27|issue=3|pages=455–465|doi=10.1038/s41431-018-0291-3|issn=1476-5438}}</ref> Stating that the highly variable penetrance of X-linked traits in females as a result of mechanisms such as skewed X-inactivation or [[somatic mosaicism]] is difficult to reconcile with standard definitions of dominance and recessiveness, scholars have suggested referring to traits on the x chromosome simply as ''X-Linked.''<ref name=":0" />

A few scholars have suggested discontinuing the use of the terms ''dominant'' and ''recessive'' when referring to X-linked inheritance, stating that the highly variable penetrance of X-linked traits in females as a result of mechanisms such as skewed X-inactivation or [[somatic mosaicism]] is difficult to reconcile with standard definitions of dominance and recessiveness.<ref>{{cite journal|last1=Dobyns|first1=William B.|last2=Filauro|first2=Allison|last3=Tomson|first3=Brett N.|last4=Chan|first4=April S.|last5=Ho|first5=Allen W.|last6=Ting|first6=Nicholas T.|last7=Oosterwijk|first7=Jan C.|last8=Ober|first8=Carole|year=2004|title=Inheritance of most X-linked traits is not dominant or recessive, just X-linked|journal=American Journal of Medical Genetics|volume=129A|issue=2|pages=136|doi=10.1002/ajmg.a.30123|pmid=15316978}}</ref>

==Examples==