Wikipedia

Genetic disorder

(Redirected fromGenetic defects)

For a list of genetic disorders, seeList of genetic disorders.

Agenetic disorderis a health problem caused by one or more abnormalities in thegenome.It can be caused by amutationin a singlegene(monogenic) or multiple genes (polygenic) or by achromosome abnormality.Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene orchromosome.[1][2]The mutation responsible can occur spontaneously beforeembryonic development(ade novomutation), or it can beinheritedfrom two parents who are carriers of a faulty gene (autosomal recessiveinheritance) or from a parent with the disorder (autosomal dominantinheritance). When the genetic disorder is inherited from one or both parents, it is also classified as ahereditary disease.Some disorders are caused by a mutation on theX chromosomeand haveX-linkedinheritance. Very few disorders are inherited on theY chromosomeormitochondrial DNA(due to their size).[3]

Genetic disorder
Diagram featuring examples of a disease located on each chromosome
SpecialtyMedical genetics

There are well over 6,000 known genetic disorders,[4]and new genetic disorders are constantly being described in medical literature.[5]More than 600 genetic disorders are treatable.[6]Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by achromosomal disorder.[7]Around 65% of people have some kind of health problem as a result of congenital genetic mutations.[7]Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare"(usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.[5][8]

Genetic disorders are present before birth, and some genetic disorders producebirth defects,but birth defects can also bedevelopmentalrather thanhereditary.The opposite of a hereditary disease is anacquired disease.Mostcancers,although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Somecancer syndromes,however, such asBRCAmutations,are hereditary genetic disorders.[9]

Single-gene

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Prevalence of some single-gene disorders[10]
Disorder prevalence (approximate)
Autosomal dominant
Familial hypercholesterolemia 1 in 500[11]
Myotonic dystrophy type 1 1 in 2,100[12]
Neurofibromatosis type I 1 in 2,500[13]
Hereditary spherocytosis 1 in 5,000
Marfan syndrome 1 in 4,000[14]
Huntington's disease 1 in 15,000[15]
Autosomal recessive
Sickle cell anaemia 1 in 625[16]
Cystic fibrosis 1 in 2,000
Tay–Sachs disease 1 in 3,000
Phenylketonuria 1 in 12,000
Autosomal recessive polycystic kidney disease 1 in 20,000[17]
Mucopolysaccharidoses 1 in 25,000
Lysosomal acid lipase deficiency 1 in 40,000
Glycogen storage diseases 1 in 50,000
Galactosemia 1 in 57,000
X-linked
Duchenne muscular dystrophy 1 in 5,000
Hemophilia 1 in 10,000
Values are for liveborn infants
See also:Oligogenic inheritanceandPolygenic inheritance

Asingle-gene disorder(ormonogenic disorder) is the result of a singlemutatedgene. Single-gene disorders can be passed on to subsequent generations in several ways.Genomic imprintinganduniparental disomy,however, may affect inheritance patterns. The divisions betweenrecessive and dominanttypes are not "hard and fast", although the divisions betweenautosomalandX-linkedtypes are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form ofdwarfism,achondroplasia,is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics could be considered carriers for.Sickle cell anemiais also considered a recessive condition, butheterozygouscarriers have increased resistance tomalariain early childhood, which could be described as a related dominant condition.[18]When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so throughin vitrofertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.[19]

Most congenitalmetabolicdisorders known asinborn errors of metabolismresult from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.[20]

Autosomal dominant

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Main article:Autosomal dominant § Autosomal dominant gene

Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.[21]: 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reducedpenetrance,which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder areHuntington's disease,[21]: 58 neurofibromatosis type 1,neurofibromatosis type 2,Marfan syndrome,hereditary nonpolyposis colorectal cancer,hereditary multiple exostoses(a highly penetrant autosomal dominant disorder),tuberous sclerosis,Von Willebrand disease,andacute intermittent porphyria.Birth defects are also called congenital anomalies.[22]

Autosomal recessive

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Main article:Autosomal dominant § Autosomal recessive allele

Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to asgenetic carriers.Each parent with a defective gene normally do not have symptoms.[23]Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder arealbinism,medium-chain acyl-CoA dehydrogenase deficiency,cystic fibrosis,sickle cell disease,Tay–Sachs disease,Niemann–Pick disease,spinal muscular atrophy,andRoberts syndrome.Certain other phenotypes, such as wet versus dryearwax,are also determined in an autosomal recessive fashion.[24][25]Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to aslight protectionagainst an infectious disease ortoxinsuch astuberculosisormalaria.[26]Such disorders include cystic fibrosis,[27]sickle cell disease,[28]phenylketonuria[29]andthalassaemia.[30]

  • Hereditary defects inenzymesare generally inherited in an autosomal fashion because there are more non-X chromosomes than X-chromosomes, and a recessive fashion because the enzymes from the unaffected genes are generally sufficient to prevent symptoms in carriers.
  • On the other hand, hereditary defects in structural proteins (such asosteogenesis imperfecta,Marfan's syndromeand manyEhlers–Danlos syndromes) are generally autosomal dominant, because it is enough that some components are defective to make the whole structure dysfunctional. This is adominant-negativeprocess, wherein a mutated gene product adversely affects the non-mutated gene product within the same cell.

X-linked dominant

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Schematickaryogramshowing an overview of thehuman genome.It shows annotatedbands and sub-bandsas used in thenomenclature of genetic disorders.It shows 22homologous chromosomes,both the female (XX) and male (XY) versions of thesex chromosome(bottom right), as well as themitochondrial genome(to scale at bottom left).[citation needed]
Further information:Karyotype
Main article:X-linked dominant

X-linked dominant disorders are caused by mutations in genes on theX chromosome.Only a few disorders have this inheritance pattern, with a prime example beingX-linked hypophosphatemic rickets.Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such asRett syndrome,incontinentia pigmentitype 2, andAicardi syndrome,are usually fatal in males eitherin uteroor shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys withKlinefelter syndrome(44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.

X-linked recessive

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Main article:X-linked recessive inheritance

X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseaseshemophilia A,Duchenne muscular dystrophy,andLesch–Nyhan syndrome,as well as common and less serious conditions such asmale pattern baldnessand red–greencolor blindness.X-linked recessive conditions can sometimes manifest in females due toskewed X-inactivationor monosomy X (Turner syndrome).[citation needed]

Y-linked

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Main article:Y linkage

Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.[citation needed]

Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.

Mitochondrial

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Main articles:Mitochondrial diseaseandMitochondrial DNA

This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded bymitochondrial DNA.Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder isLeber's hereditary optic neuropathy.[31]

It is important to stress that the vast majority ofmitochondrial diseases(particularly when symptoms develop in early life) are actually caused by anuclear genedefect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.[32]

Multifactorial disorder

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Main article:Multifactorial disease

Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders includeheart diseaseanddiabetes.Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determinegenotype–phenotypeassociations. One method, thegenotype-first approach,starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinicalheterogeneity,penetrance,and expressivity.[citation needed]

On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as withMendeliandiseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g.,blood pressure).

Other such cases include:

Chromosomal disorder

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See also:Chromosome abnormality
Chromosomes inDown syndrome,the most common human condition due to aneuploidy. There are three chromosomes 21 (in the last row).

A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA.[33]It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form ofDown syndrome), in which there is an extra copy of chromosome 21 in all cells.[34]

Diagnosis

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Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosedpre-birth,at birth,or during early childhood however some, such asHuntington's disease,can escape detection until the patient begins exhibiting symptoms well into adulthood.[35]

The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depthfamily history,it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility ofstillbirth,or contemplatetermination.[36]Prenatal diagnosiscan detect the presence of characteristic abnormalities in fetal development throughultrasound,or detect the presence of characteristic substances viainvasive procedureswhich involve inserting probes or needles into the uterus such as inamniocentesis.[37]

Prognosis

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Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such asDown syndrome,while others result in purely physical symptoms such asmuscular dystrophy.Other disorders, such asHuntington's disease,show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation ofquality of lifeand maintain patientautonomy.This includesphysical therapyandpain management.

Treatment

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Frompersonal genomicsto gene therapy
See also:Gene therapy

The treatment of genetic disorders is an ongoing battle, with over 1,800gene therapyclinical trials having been completed, are ongoing, or have been approved worldwide.[38]Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patientquality of life.

Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder.[39]

Epidemiology

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Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by achromosomal disorder.[7]Around 65% of people have some kind of health problem as a result of congenital genetic mutations.[7]Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare"(usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.[5][8]There are well over 6,000 known genetic disorders,[4]and new genetic disorders are constantly being described in medical literature.[5]

History

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The earliest known genetic condition in ahominidwas in the fossil speciesParanthropus robustus,with over a third of individuals displayingamelogenesis imperfecta.[40]

See also

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References

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  1. ^"Genetic Disorders".Learn.Genetics.University of Utah.Archivedfrom the original on 2022-07-15.
  2. ^Lvovs D, Favorova OO, Favorov AV (July 2012)."A Polygenic Approach to the Study of Polygenic Diseases".Acta Naturae.4(3): 59–71.doi:10.32607/20758251-2012-4-3-59-71.PMC3491892.PMID23150804.
  3. ^"What are the different ways in which a genetic condition can be inherited?".Genetics Home Reference.Archived fromthe originalon 2020-09-27.Retrieved2020-01-14.
  4. ^ab"OMIM Gene Map Statistics".OMIM.Archivedfrom the original on 2020-01-28.Retrieved2020-01-14.
  5. ^abcd"About rare diseases".Orphanet.Archivedfrom the original on 2019-12-17.Retrieved2020-01-14.
  6. ^Bick D, Bick SL, Dimmock DP, Fowler TA, Caulfield MJ, Scott RH (March 2021)."An online compendium of treatable genetic disorders".American Journal of Medical Genetics. Part C, Seminars in Medical Genetics.187(1): 48–54.doi:10.1002/ajmg.c.31874.PMC7986124.PMID33350578.
  7. ^abcdKumar P, Radhakrishnan J, Chowdhary MA, Giampietro PF (August 2001). "Prevalence and patterns of presentation of genetic disorders in a pediatric emergency department".Mayo Clinic Proceedings.76(8): 777–783.doi:10.4065/76.8.777.PMID11499815.
  8. ^abJackson M, Marks L, May GH, Wilson JB (December 2018)."The genetic basis of disease".Essays in Biochemistry.62(5): 643–723.doi:10.1042/EBC20170053.PMC6279436.PMID30509934.(calculated from "1 in 17" rare disorders and "80%" of rare disorders being genetic)
  9. ^Hunt JD."An Introduction to Cancer".Genetics and Louisiana Families.lsuhsc.edu. Archived fromthe originalon 16 January 2020.
  10. ^"Prevalence and incidence of rare diseases"(PDF).Archived(PDF)from the original on 2008-11-18.
  11. ^"OMIM Entry #144010 – HYPERCHOLESTEROLEMIA, FAMILIAL, 2; FCHL2".omim.org.Archivedfrom the original on 2021-03-09.Retrieved2019-07-01.
  12. ^Johnson NE, Butterfield RJ, Mayne K, Newcomb T, Imburgia C, Dunn D, et al. (February 2021)."Population-Based Prevalence of Myotonic Dystrophy Type 1 Using Genetic Analysis of Statewide Blood Screening Program".Neurology.96(7): e1045–e1053.doi:10.1212/WNL.0000000000011425.PMC8055332.PMID33472919.
  13. ^"OMIM Entry #162200 – NEUROFIBROMATOSIS, TYPE I; NF1".omim.org.Archivedfrom the original on 2021-03-08.Retrieved2019-07-01.
  14. ^Keane MG, Pyeritz RE (May 2008). "Medical management of Marfan syndrome".Circulation.117(21): 2802–2813.doi:10.1161/CIRCULATIONAHA.107.693523.PMID18506019.
  15. ^Walker FO (January 2007). "Huntington's disease".Lancet.369(9557): 218–228.doi:10.1016/S0140-6736(07)60111-1.PMID17240289.S2CID46151626.
  16. ^"OMIM Entry #603903 – SICKLE CELL ANEMIA".omim.org.Archivedfrom the original on 2021-04-26.Retrieved2019-07-01.
  17. ^Swanson K (November 2021)."Autosomal recessive polycystic kidney disease".American Journal of Obstetrics and Gynecology.225(5). Elsevier BV: B7–B8.doi:10.1016/j.ajog.2021.06.038.PMID34507795.S2CID237480065.
  18. ^Williams TN, Obaro SK (July 2011). "Sickle cell disease and malaria morbidity: a tale with two tails".Trends in Parasitology.27(7): 315–320.doi:10.1016/j.pt.2011.02.004.PMID21429801.
  19. ^Kuliev A, Verlinsky Y (April 2005). "Preimplantation diagnosis: a realistic option for assisted reproduction and genetic practice".Current Opinion in Obstetrics & Gynecology.17(2): 179–183.doi:10.1097/01.gco.0000162189.76349.c5.PMID15758612.S2CID9382420.
  20. ^Šimčíková D, Heneberg P (December 2019)."Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases".Scientific Reports.9(1): 18577.Bibcode:2019NatSR...918577S.doi:10.1038/s41598-019-54976-4.PMC6901466.PMID31819097.
  21. ^abGriffiths AJ, Wessler SR, Carroll SB, Doebley J (2012). "2: Single-Gene Inheritance".Introduction to Genetic Analysis(10th ed.). New York: W.H. Freeman and Company.ISBN978-1-4292-2943-2.
  22. ^Malherbe HL, Modell B, Blencowe H, Strong KL, Aldous C (June 2023)."A review of key terminology and definitions used for birth defects globally".Journal of Community Genetics.14(3): 241–262.doi:10.1007/s12687-023-00642-2.PMC10272040.PMID37093545.
  23. ^"Inheritance Patterns for Single Gene Disorders".learn.genetics.utah.edu.Archivedfrom the original on 2019-07-01.Retrieved2019-07-01.
  24. ^Wade N (29 January 2006)."Japanese Scientists Identify Ear Wax Gene".The New York Times.Archivedfrom the original on 21 March 2023.Retrieved20 February2023.
  25. ^Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, et al. (March 2006). "A SNP in the ABCC11 gene is the determinant of human earwax type".Nature Genetics.38(3): 324–330.doi:10.1038/ng1733.PMID16444273.S2CID3201966.
  26. ^Mitton JB (2002). "Heterozygous Advantage".eLS.doi:10.1038/npg.els.0001760.ISBN978-0-470-01617-6.
  27. ^Poolman EM, Galvani AP (February 2007)."Evaluating candidate agents of selective pressure for cystic fibrosis".Journal of the Royal Society, Interface.4(12): 91–98.doi:10.1098/rsif.2006.0154.PMC2358959.PMID17015291.
  28. ^Allison AC (October 2009). "Genetic control of resistance to human malaria".Current Opinion in Immunology.21(5): 499–505.doi:10.1016/j.coi.2009.04.001.PMID19442502.
  29. ^Woolf LI(May 1986)."The heterozygote advantage in phenylketonuria".American Journal of Human Genetics.38(5): 773–775.PMC1684820.PMID3717163.
  30. ^Weatherall DJ (2015)."The Thalassemias: Disorders of Globin Synthesis".Williams Hematology(9e ed.). McGraw Hill Professional. p. 725.ISBN978-0-07-183301-1.Archivedfrom the original on 2023-02-20.Retrieved2023-02-20.
  31. ^Shemesh A, Sood G, Margolin E."Leber Hereditary Optic Neuropathy (LHON)".StatPearls [Internet].Treasure Island (FL): StatPearls Publishing.
  32. ^Nussbaum R, McInnes R, Willard H (2007).Thompson & Thompson Genetics in Medicine.Philadelphia PA: Saunders. pp. 144, 145, 146.ISBN978-1-4160-3080-5.
  33. ^"Genetic Disorders: What Are They, Types, Symptoms & Causes".Cleveland Clinic.Archivedfrom the original on 2023-11-01.Retrieved2023-11-01.
  34. ^CDC (2023-10-10)."Facts about Down Syndrome | CDC".Centers for Disease Control and Prevention.Archivedfrom the original on 2017-07-28.Retrieved2023-11-01.
  35. ^Wyant KJ, Ridder AJ, Dayalu P (April 2017). "Huntington's Disease-Update on Treatments".Current Neurology and Neuroscience Reports.17(4): 33.doi:10.1007/s11910-017-0739-9.PMID28324302.
  36. ^Milunsky A, Milunsky JM (2021). "Genetic Counseling: Preconception, Prenatal, and Perinatal".Genetic Disorders and the Fetus.pp. 1–101.doi:10.1002/9781119676980.ch1.ISBN978-1-119-67698-0.
  37. ^"Diagnostic Tests – Amniocentesis".Harvard Medical School. Archived fromthe originalon 2008-05-16.Retrieved2008-07-15.
  38. ^Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J (February 2013). "Gene therapy clinical trials worldwide to 2012 - an update".The Journal of Gene Medicine.15(2): 65–77.doi:10.1002/jgm.2698.PMID23355455.S2CID37123019.
  39. ^Verma IM (August 2013). "Medicine. Gene therapy that works".Science.341(6148): 853–855.Bibcode:2013Sci...341..853V.doi:10.1126/science.1242551.PMID23970689.S2CID206550787.
  40. ^Towle I, Irish JD (April 2019)."A probable genetic origin for pitting enamel hypoplasia on the molars of Paranthropus robustus"(PDF).Journal of Human Evolution.129:54–61.doi:10.1016/j.jhevol.2019.01.002.PMID30904040.S2CID85502058.Archived(PDF)from the original on 2023-06-04.Retrieved2023-02-20.
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