All Creatures Great and Small: New Approaches for Understanding Down Syndrome Genetics

Abstract

Down syndrome (DS) is caused by an extra copy of ~500 genes.Understanding how human chromosome 21 (Hsa21) genes contribute to DS phenotypes is essential for developing effective treatment strategies.Many Hsa21 genes functionally interact, and overexpression of these genes perturbs expression of genes throughout the genome.DS research has focused on only a few Hsa21 genes.Diverse model organisms from yeast to mice are being used to study the effects of aneuploidy, to annotate functions of Hsa21 orthologs, and to model aspects of DS pathology. Human chromosome 21 (Hsa21) contains more than 500 genes, making trisomy 21 one of the most complex genetic perturbations compatible with life. The ultimate goal of Down syndrome (DS) research is to design therapies that improve quality of life for individuals with DS by understanding which subsets of Hsa21 genes contribute to DS-associated phenotypes throughout the lifetime. However, the complexity of DS pathogenesis has made developing appropriate animal models an ongoing challenge. Here, we examine lessons learned from a variety of model systems, including yeast, nematode, fruit fly, and zebrafish, and discuss emerging methods for creating murine models that better reflect the genetic basis of trisomy 21. Human chromosome 21 (Hsa21) contains more than 500 genes, making trisomy 21 one of the most complex genetic perturbations compatible with life. The ultimate goal of Down syndrome (DS) research is to design therapies that improve quality of life for individuals with DS by understanding which subsets of Hsa21 genes contribute to DS-associated phenotypes throughout the lifetime. However, the complexity of DS pathogenesis has made developing appropriate animal models an ongoing challenge. Here, we examine lessons learned from a variety of model systems, including yeast, nematode, fruit fly, and zebrafish, and discuss emerging methods for creating murine models that better reflect the genetic basis of trisomy 21. Down syndrome (DS) comprises a collection of phenotypic features that are common in individuals who inherit an extra copy of all or, rarely, part of the long arm of human chromosome 21. All individuals with DS display some level of intellectual disability and will develop the neuropathology of Alzheimer’s disease (AD) at an early age. They also present with hypotonia, cerebellar hypoplasia, and midface skeletal retrusion. Additional common, but not universal, features include congenital heart defects, abnormalities in immune system function, thyroid deficiency, childhood leukemia, and early-onset dementia [1.Capone G.T. Down syndrome: advances in molecular biology and the neurosciences.J. Dev. Behav. Pediatr. 2001; 22: 40-59Crossref PubMed Scopus (89) Google Scholar,2.Antonarakis S.E. et al.Down syndrome.Nat. Rev. Dis. Primers. 2020; 6: 9Crossref PubMed Scopus (92) Google Scholar]. Sex differences have been noted in some features. For example, males are more impaired in the acquisition of cognitive and language skills than are females [3.Kittler P. et al.Sex differences in performance over 7 years on the Wechsler Intelligence Scale for Children - revised among adults with intellectual disability.J. Intellect. Disabil. Res. 2004; 48: 114-122Crossref PubMed Scopus (33) Google Scholar, 4.Aoki S. et al.Developmental trend of children with Down's syndrome - how do sex and neonatal conditions influence their developmental patterns?.Brain and Development. 2018; 40: 181-187Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 5.Startin C.M. et al.Health comorbidities and cognitive abilities across the lifespan in Down syndrome.J. Neurodev. Disord. 2020; 12: 4Crossref PubMed Scopus (30) Google Scholar, 6.Maatta T. et al.Mental health, behaviour and intellectual abilities of people with Down syndrome.Downs Syndr. Res. Pract. 2006; 11: 37-43Crossref PubMed Scopus (74) Google Scholar]. Conversely, congenital heart defects are seen more frequently in females [7.Morris J.K. et al.Major congenital anomalies in babies born with Down syndrome: a EUROCAT population-based registry study.Am. J. Med. Genet. A. 2014; 164A: 2979-2986Crossref PubMed Scopus (42) Google Scholar, 8.Takano T. et al.Sex differences in congenital heart disease in Down syndrome: study data from medical records and questionnaires in a of PubMed Scopus Google Scholar, et al.Sex differences for congenital heart defects in Down a J. Med. Genet. 2018; PubMed Scopus Google Scholar]. that the of DS at more than one in a and medical et and of defects in the Res. 2006; PubMed Scopus Google et in and of Down J. Genet. PubMed Scopus Google Scholar]. The to DS research has been to on understanding which subsets of human chromosome 21 genes contribute to phenotypic features and to develop therapies to these the of the advances in understanding and have the complex of Hsa21 genes genes, a of and genes that et models of Down syndrome: and PubMed Scopus Google Scholar]. The functions of most Hsa21 genes, are of these genes to trisomy in the and and of most and organisms are essential for functions and for creating models of has long been the model of for has and complex organisms are being among fruit and yeast the of these systems, is to the and of Here, we discuss of Hsa21 genes among these organisms and that have on the functions of Hsa21 genes and how their in to the features of Hsa21 is the of human the human chromosome to et of human chromosome 2001; Google has been et models of Down syndrome: and PubMed Scopus Google et years Res. 2014; PubMed Scopus Google Scholar]. that the to the phenotypes of The most of the long which ~500 genes are genes, of the of and that which not that expression of genes is to and the include these genes are not the genes are of the and with sex differences in and to including the and that et models of Down syndrome: and PubMed Scopus Google Scholar]. of these are from to genes throughout the few Hsa21 have been have been for and in the of trisomy 21. of genes in model organisms of the being a their of Hsa21 genes with in a is is with with genes genes are genes in the of the of chromosome in an of and genes in an of et on human chromosome 2001; PubMed Scopus Google Scholar]. the with is on chromosome the with and are on genes are to all expression to for Hsa21 with Hsa21 the of by of that are and to Hsa21 that are will Hsa21 orthologs, that are will and differences in differences in differences for example, and are in and that in of differences in only one is in copy of a have is a Hsa21 is a of a a in and in has in some Hsa21 genes with in and to in trisomy most in a in and level a in expression with in models of the and of genes trisomy of in with one of genes in the the models has phenotypic and the of the for the Hsa21 is by of trisomy of the of a with trisomy of only one Hsa21 the Hsa21 and are of the Hsa21 and the to which is for on Sex some phenotypes in DS in males and animal of males and females of of DS trisomy of human of S. et Down syndrome: a study of trisomy in a PubMed Scopus Google with of human overexpression of genes model for animal some that are more in of with overexpression of genes, of human of genes in overexpression of genes phenotypes in systems, and of genes, developmental of one a few genes is to a genes and are and have in phenotypes caused by of and and in most genes of one a few genes is to a genes and are and have in and and of one a few genes is to a genes and are and have in and expression of genes, effects of on perturbations to in a in of Hsa21 and expression and are for Hsa21 of model in the of in the by not with of to of the in the and of expression in in a only over and and and and expression in to not an for in to expression in and also contains of an overexpression contains an in a in overexpression in cerebellar and a genes are on contains a with in immune and in and in and and expression and are for Hsa21 of model in the of in the by not with of to in a with Hsa21 the of by of that are and to Hsa21 that are will Hsa21 orthologs, that are will and differences in differences in differences for example, and are in and that in of differences in only one is in copy of a have is a Hsa21 is a of a a in and in has in some Hsa21 genes with in and to DS in trisomy most in a in and level a in expression with in models of the and of genes trisomy of in with one of genes in the the models has phenotypic and the of the for the Hsa21 is by of trisomy of the of a with trisomy of only one Hsa21 the Hsa21 and are of the Hsa21 and the to which is for on Sex some phenotypes in DS in males and animal of males and females For model not only of but also a only a of the is the model seen in the Hsa21 the with features seen in the Hsa21 is expression expression in one and expression in the have for is the of For example, a in with a Hsa21 and human that the of the that of the Hsa21 Hsa21 to a of the and used to are in For effective DS in model of some is genes, is and expression are than the of seen in of present a of a are are for but of and of to DS with do not reflect in but the of a of in a system that the DS also the effects of and the of has been by the phenotypes of models for the also in the for in the of and of Hsa21 et abnormalities and cognitive in mice a murine model of Down's Genet. 2001; PubMed Scopus Google Scholar, et for the Down syndrome is but not for phenotypes of Genet. PubMed Scopus Google Scholar, et of the Down syndrome Genet. PubMed Scopus Google Scholar]. is that of the are by Hsa21 T. et the of with Res. 2006; PubMed Scopus Google et of for a Down syndrome and PubMed Scopus Google Scholar]. The of expression of a of which are by expression of from with in The more models are to in organisms than to and to Hsa21 genes is that of Hsa21 from genes that contribute to DS features. The not to at the and et al.Down syndrome the of S. A. PubMed Scopus Google et genetic of Down syndrome phenotypes by of human S. A. PubMed Scopus Google Scholar]. the of including the of intellectual has been made in of trisomy Hsa21 the the et genetic of Down syndrome phenotypes by of human S. A. PubMed Scopus Google Scholar]. a of Hsa21 the a among DS to trisomy et of trisomy 21 with Down syndrome a on to the Genet. Google et trisomy 21 the Down syndrome on human chromosome Med. PubMed Scopus Google Scholar]. genetic are in the and for only has been The has intellectual phenotypic than the for all the et genetic of Down syndrome phenotypes by of human S. A. PubMed Scopus Google Scholar]. all Hsa21 genes the of phenotypes are caused by of which contains of genes that are with and developmental at DS phenotypes are display in only some people with and in among people with how trisomy 21 the features of DS to of DS the and of genes and genetic is For example, on a that a Hsa21 that overexpression of the is to a in the of the effects of genes a model system Hsa21 genes are a to in the of trisomy a is to the in the of that Conversely, the to a in a model not that have in have a of how Hsa21 genes contribute to DS the of these genes, the of a Here, we of how Hsa21 genes a in a in Hsa21 genes in which However, few Hsa21 genes have been to have a models are the to and but from these models in that better reflect the complex genetic basis of of model is that Hsa21 genes have effects on a and that the is the of these genes these effects is overexpression of genes a overexpression of has on the of the of and in Hsa21 genes with DS of Human 21 (Hsa21) in is only among Hsa21 are on chromosome on of and and on and However, in zebrafish, fruit fly, and nematode, Hsa21 are throughout the one and ~500 of that is not to The genes and are in a in the of contains an among DS-associated phenotypes are caused by of which contains of genes that are with and developmental at DS phenotypes are display in only some people with and in among people with how trisomy 21 the features of DS to of DS the and of genes and genetic is For example, on a that a Hsa21 that overexpression of the is to a in the of the effects of genes a model system Hsa21 genes are a to in the of trisomy a is to the in the of that Conversely, the to a in a model not that have in have a of how Hsa21 genes contribute to DS the of these genes, the of a Here, we of how Hsa21 genes a in a The in Hsa21 genes in which However, few Hsa21 genes have been to have a models are the to and but from these models in that better reflect the complex genetic basis of of model is that Hsa21 genes have effects on a and that the is the of these genes these effects is overexpression of genes a overexpression of has on the of the of and in Hsa21 genes with DS is only among Hsa21 are on chromosome on of and and on and However, in zebrafish, fruit fly, and nematode, Hsa21 are throughout the one and ~500 of that is not to The genes and are in a in the of contains an among the in design and the and of in yeast, nematode, fruit fly, and have in DS these organisms the functions of Hsa21 genes and their effects on genes and in some the and of of how their human contribute to the phenotypic features of DS research has focused on the effects of Hsa21 genes, but some features from an extra chromosome of the genes that Down syndrome - a of J. Med. Genet. PubMed Scopus Google the basis for Down syndrome Genet. 2006; PubMed Scopus Google Scholar]. is to in models all are However, the yeast some and is an system for the effects of et in Res. Google Scholar]. yeast are not a model of but the effects of that to some DS features with that have effects on et et of on and in PubMed Scopus Google a collection of yeast that at one extra copy of a yeast is an with of chromosome more than and that the expression of a of genes to that of the yeast et S.E. et and effects of in PubMed Scopus (30) Google on by that the of of some genes the of of genes the of For example, of of the complex the of but a on of which a impaired the of and emerging of that the phenotypes from the of to and in J. et with 2018; Full Text Full Text PDF PubMed Scopus Google a to et C.M. et of in Dev. PubMed Scopus Google in yeast some of to the of the et et defects of PubMed Scopus Google that of have a that is of with these that some phenotypes from are the of of of DS pathogenesis that of phenotypic among people with DS with the Down syndrome - a of J. Med. Genet. PubMed Scopus Google Scholar]. et et Full Text Full Text PDF PubMed Scopus Google in yeast by across the which The that of these more in and more in to perturbations than of these made in with a copy of a chromosome which with of one chromosome these are with phenotypic The a model system for genetic of and the The is which and is to a variety of genetic the of of the and the of of the are of the nematode, PubMed Scopus Google Scholar, et of the PubMed Scopus Google Scholar, et of the system of the PubMed Google Scholar]. have been and genetic in early with defects in and S. The of PubMed Google Scholar]. models of human including have been et of a model to study disease and Genet. 2014; PubMed Scopus Google Scholar]. some disease models human these genes and their to their in of human genes have orthologs, but of Hsa21 genes are throughout the of of is to that are for of Hsa21 a of genes with human PubMed Scopus Google of the a for PubMed Scopus Google Scholar]. is not used to study some of Hsa21 genes have been in and models of overexpression for in DS-associated et of is and cognitive and in models of PubMed Scopus Google Scholar]. of the Human a for and of early phenotypes caused by of the of Hsa21 For example, of the of caused of and et a human chromosome 21 has a for PubMed Scopus Google Scholar]. phenotypes caused by copy of and have also been et of of the Down syndrome PubMed Google Scholar, et of a is for 2004; PubMed Scopus Google Scholar, et of in PubMed Scopus Google Scholar, et in PubMed Scopus Google Scholar, et at the and functions in with PubMed Scopus (30) Google Scholar, et a in PubMed Scopus Google Scholar]. et et of human chromosome in 2018; PubMed Scopus Google to the of Hsa21 genes by and in with in of Hsa21 Hsa21 genes for and The of is by of genes in and of the Hsa21 by the in of the is to of expression and on for of the For example, the that of a of in an and that expression is to However, the human and only over only of the with in and expression has been in et of in Down syndrome model PubMed Scopus Google et of expression in the PubMed Scopus Google Scholar]. will to with and human For has the of an of genetic of and of creating with trisomy for of Hsa21 is of their throughout the are for the functions of genes, genetic of Hsa21 orthologs, the and molecular by which overexpression and genetic of these have focused on the of and Here, we to of and to genetic Hsa21 The which an is for for the to by of et is an molecular Full Text Full Text PDF PubMed Scopus Google Scholar]. and the expression of of and et and of PubMed Scopus Google Scholar, et is essential for and PubMed Scopus Google Scholar, et of from of Full Text Full Text PDF PubMed Scopus Google Scholar, P. et for and Full Text Full Text PDF PubMed Scopus Google Scholar]. The of in and defects, but not all of these defects are caused by the of et complex Full Text Full Text PDF PubMed Scopus Google J. et is for of and of Full Text Full Text PDF PubMed Scopus Google Scholar]. For example, in the expression level of of the et expression in Full Text Full Text PDF PubMed Scopus Google Scholar]. et et to Scopus Google that of and that of the defects caused by the only a few contribute to and in et and in in in the developing Full Text Full Text PDF PubMed Scopus Google Scholar, et in Down 2020; Scholar, et functions a in S. A. PubMed Scopus Google Scholar, et Down syndrome PubMed Scopus Google Scholar, et and in the developing S. A. PubMed Scopus Google Scholar, et and and system Dev. 2018; PubMed Scopus Google Scholar, et a of the in a Down syndrome and is in the of the Genet. PubMed Scopus Google Scholar]. The of a the of functions for in and complex genes in complex Dev. PubMed Scopus Google for subsets of Hsa21 genes have effects on DS phenotypes but these in models is and is for of at the and molecular that and are in the of individuals with and of of human chromosome 21 genes for Down S. A. PubMed Scopus Google all of their from in and and of all to a in at the a et et of and congenital heart Genet. PubMed Scopus Google all of human and in the of and caused more phenotypes than overexpression of in are by and For example, the of and all in some of which are to include However, of genes in these for how of Hsa21 to the complex phenotypes of has a system for the effects of genes on is a developing from to in et of of the PubMed Scopus Google The for the of of Scholar]. are for The has been and with including However, has a making some genes and their with the in and of the of expression in by with some and a to et PubMed Scopus Google Scholar]. expression also for of the of to the and of in most all of the early developing The to early of is in to of of and to that have been used to for have been used and in 2014; PubMed Scopus Google Scholar]. The to early has been used to the of to on the of to the effects of et S. et of human chromosome 21 expression effects on early in 2018; PubMed Scopus Google a of Hsa21 genes in that of made from of these the and the for effects on heart and that are is and Hsa21 the of one more of these genes on long caused and with of genes a and The not a in but the of the of with to than seen with The of effects of Hsa21 overexpression in DS has been for some and are from but of with genes these the effects of Hsa21 genes on to in study not reflect DS in that genes at most and that overexpression of of the has of and of which in a with for genetic the has made to understanding the of in the model to the effects of on features to DS et trisomy a model for Down Res. Google Scholar, et trisomy of murine chromosome a model system for Down Res. Google Scholar, et model for Down syndrome and behaviour Genet. 11: PubMed Scopus Google Scholar]. has a on DS is for only of genes of more the chromosome has a copy of genes that are not Hsa21 et of the in the Down syndrome model 22: PubMed Scopus Google A. et of the in the and for Down 22: PubMed Scopus Google Scholar]. the of more than models have been to study the effects of trisomy of Hsa21 genes their The and of DS models have been et models of Down syndrome: and PubMed Scopus Google et models in Down syndrome and PubMed Scopus Google et Down syndrome in from the early to the models and Res. 2020; PubMed Scopus Google Scholar]. Here, we discuss emerging for creating murine models that better reflect the genetic basis of trisomy chromosome and et T. et a human chromosome 21 model and anomalies of Down's Genet. 2001; PubMed Scopus Google the of a copy of Hsa21 which used to mice with some features. et A. et human chromosome 21 with Down syndrome PubMed Scopus Google the model to and Hsa21 the to of of Hsa21 genes, the of model is the human making a of and A. et human chromosome 21 with Down syndrome PubMed Scopus Google et the complex of an human chromosome on a in the model of Down PubMed Scopus Google Scholar]. the model by a chromosome to et model of Down syndrome the long arm of human chromosome 2020; PubMed Scopus Google Scholar]. mice a copy of are not and features of trisomy with models and human that to the of the human chromosome in a for creating models part all of have been human and their in models to the of trisomy on and et et of human and Down 2018; PubMed Scopus Google from individuals with DS with of and these over the of of with of et et phenotypes in human and models of Down Full Text Full Text PDF PubMed Scopus Google from made from individuals with trisomy 21 a The DS that the to expression of the Hsa21 these of expression in the that of a few to with the developmental that a and the of a few not to few genes of in the of of that reflect some aspects of the from trisomy the of these do not and will not the of genetic that have been in advances in and have their S. et to the PubMed Scopus (33) Google Scholar]. have been and for in to disease and complex and are to human disease for some of than are mice S. models of human for therapies and to the with Res. Rev. Scopus Google Scholar]. to have with mice of for and for for with mice is for and and for to in et in 2018; PubMed Scopus Google Scholar]. a model of DS has to et et and of in and mice PubMed Scopus Google of of the to models on methods used to Hsa21 to are A. et human chromosome 21 with Down syndrome PubMed Scopus Google et model of Down syndrome the long arm of human chromosome 2020; PubMed Scopus Google Scholar]. models are essential to understanding the complex of the overexpression of of genes in The most appropriate model for research to DS on the at and are for of Hsa21 orthologs, and zebrafish, with some these the of models emerging developing and that reflect aspects of human models of DS are is model of and appropriate models for a goal For the are features that in which model to is have an chromosome is by that the of and aspects of are not is the extra genetic and present in genes are is that models for all of Hsa21 are of the and of genes in do human and genes have expression to the the of and to the do genes For most genes, understanding in trisomy will understanding their functions is to and a is not a The animal models are for do not have these and animal models essential for of the some in by the of and human J. et and 12: PubMed Scopus Google Scholar]. the and is to that are to reflect the features of the human and to the most to to with and to are Hsa21 genes across and developmental among individuals and are these in model Hsa21 genes contribute to which DS in Hsa21 and genes contribute to in DS the of in models an effective to model DS phenotypes in differences caused by Hsa21 are the functions of Hsa21 across yeast, fly, zebrafish, and model Hsa21 genes have effects on a DS is to their in DS than Hsa21 how Hsa21 genes is to an model of models of features in of complex these features models of DS the of human and models have in DS and to are Hsa21 genes across and developmental among individuals and are these in model Hsa21 genes contribute to which DS in Hsa21 and genes contribute to in DS the of in models an effective to model DS phenotypes in differences caused by Hsa21 are the functions of Hsa21 across yeast, fly, zebrafish, and model Hsa21 genes have effects on a DS is to their in DS than Hsa21 how Hsa21 genes is to an model of models of features in of complex these features models of DS the of human and models have in DS is in part by and and by and All are the and do not reflect of the of with with in the than the chromosome of the to in genetic being of all sex the of for a of the of and are and their in a a the of which from the to from the but in most to functions an of more than one from frequently in have in of an a with a and with a a that the in a of genes a a in from of all sex for a an in which a chromosome of a is present a human chromosome in a an of the in which genetic is in which an extra chromosome is present in the

Topics & Concepts