Genetic Architecture of Protein Expression and its Regulation in the Mouse Brain

Abstract Background Natural variation in protein expression is common in all organisms and contributes to phenotypic differences among individuals. While variation in gene expression at the transcript level has been extensively investigated, the genetic mechanisms underlying variation in protein expression have lagged considerably behind. Here we investigate genetic architecture of protein expression by profiling a deep mouse brain proteome of two inbred strains, C57BL/6J (B6) and DBA/2J (D2), and their reciprocal F1 hybrids using two-dimensional liquid chromatography coupled with tandem mass spectrometry (LC/LC-MS/MS) technology. Results By comparing protein expression levels in the four mouse strains, we observed 329 statistically significant differentially expressed proteins between the two parental strains and identified four common inheritance patterns, including 1,133 dominant, 980 additive, 63 over- and 62 under-dominant expression. We further applied the proteogenomic approach to detect variant peptides and define protein allele-specific expression (pASE), identifying 33 variant peptides with cis‐effects and 17 variant peptides showing trans‐effects. Comparison of regulation at transcript and protein levels show a significant divergence. Conclusions The results provide a comprehensive analysis of genetic architecture of protein expression and the contribution of cis- and trans‐acting regulatory differences to protein expression.

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Genetic architecture of protein expression and its regulation in the mouse brain

BMC Genomics ◽

10.1186/s12864-021-08168-y ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Alyssa Erickson ◽

Suiping Zhou ◽

Jie Luo ◽

Ling Li ◽

Xin Huang ◽

...

Keyword(s):

Protein Expression ◽

Mouse Brain ◽

Genetic Architecture ◽

Transcript Level ◽

Inbred Strains ◽

F1 Hybrids ◽

Mouse Strains ◽

Specific Expression ◽

Protein Levels ◽

Brain Proteome

Abstract Background Natural variation in protein expression is common in all organisms and contributes to phenotypic differences among individuals. While variation in gene expression at the transcript level has been extensively investigated, the genetic mechanisms underlying variation in protein expression have lagged considerably behind. Here we investigate genetic architecture of protein expression by profiling a deep mouse brain proteome of two inbred strains, C57BL/6 J (B6) and DBA/2 J (D2), and their reciprocal F1 hybrids using two-dimensional liquid chromatography coupled with tandem mass spectrometry (LC/LC-MS/MS) technology. Results By comparing protein expression levels in the four mouse strains, we observed 329 statistically significant differentially expressed proteins between the two parental strains and characterized the genetic basis of protein expression. We further applied a proteogenomic approach to detect variant peptides and define protein allele-specific expression (pASE), identifying 33 variant peptides with cis-effects and 17 variant peptides showing trans-effects. Comparison of regulation at transcript and protein levels show a significant divergence. Conclusions The results provide a comprehensive analysis of genetic architecture of protein expression and the contribution of cis- and trans-acting regulatory differences to protein expression.

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Genetic epilepsy model derived from common inbred mouse strains.

Genetics ◽

10.1093/genetics/138.2.481 ◽

1994 ◽

Vol 138 (2) ◽

pp. 481-489

Author(s):

W N Frankel ◽

B A Taylor ◽

J L Noebels ◽

C M Lutz

Keyword(s):

Inbred Mouse ◽

Inbred Mouse Strain ◽

Inbred Strains ◽

Early Gene ◽

F1 Hybrids ◽

Mouse Strains ◽

Generalized Seizures ◽

Trait Locus ◽

Locus Mapping ◽

Routine Handling

Abstract The recombinant inbred mouse strain, SWXL-4, exhibits tonic-clonic and generalized seizures similar to the commonest epilepsies in humans. In SWXL-4 animals, seizures are observed following routine handling at about 80 days of age and may be induced as early as 55 days by rhythmic gentle tossing. Seizures are accompanied by rapid, bilateral high frequency spike cortical discharges and followed by a quiescent post-ictal phase. Immunohistochemistry of the immediate early gene products c-Fos and c-Jun revealed abnormal activation within cortical and limbic structures. The seizure phenotype of SWXL-4 can be explained and replicated fully by the inheritance of susceptibility alleles from its progenitor strains, SWR/J and C57L/J. Outcrosses of SWXL-4 with most other common inbred strains result in F1 hybrids that have seizure at least as frequently as SWXL-4 itself. Quantitative trait locus mapping reveals a seizure frequency determinant, Szf1, near the pink-eyed dilution locus on chromosome 7, accounting for up to 32% of the genetic variance in an F2 intercross between SWXL-4 and the linkage testing strain ABP/Le. These studies demonstrate that common strains of mice such as SWR and C57L contain latent epilepsy susceptibility alleles. Although the inheritance of susceptibility may be complex, these results imply that a number of potentially important and practical, noninvasive models for this disorder can be constructed and studied in crosses between common mouse strains.

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MAL2-Induced Actin-Based Protrusion Formation is Anti-Oncogenic in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12020422 ◽

2020 ◽

Vol 12 (2) ◽

pp. 422

Author(s):

Alfonso López-Coral ◽

Gianna-Jade del Vecchio ◽

Joeffrey J. Chahine ◽

Bhaskar V. Kallakury ◽

Pamela L. Tuma

Keyword(s):

Protein Expression ◽

Mutational Analysis ◽

Transcript Level ◽

Human Carcinoma ◽

Protein Levels ◽

Transcriptional Regulatory ◽

Human Carcinomas ◽

Transient Overexpression ◽

Regulatory Model ◽

Chromosome 8Q24

Recent studies report that the polarity gene myelin and lymphocyte protein 2 (MAL2), is overexpressed in multiple human carcinomas largely at the transcript level. Because chromosome 8q24 amplification (where MAL2 resides) is associated with hepatocellular- and cholangio-carcinomas, we examined MAL2 protein expression in these human carcinoma lesions and adjacent benign tissue using immunohistochemistry. For comparison, we analyzed renal cell carcinomas that are not associated with chromosome 8q24 amplification. Surprisingly, we found that MAL2 protein levels were decreased in the malignant tissues compared to benign in all three carcinomas, suggesting MAL2 expression may be anti-oncogenic. Consistent with this conclusion, we determined that endogenously overexpressed MAL2 in HCC-derived Hep3B cells or exogenously expressed MAL2 in hepatoma-derived Clone 9 cells (that lack endogenous MAL2) promoted actin-based protrusion formation with a reciprocal decrease in invadopodia. MAL2 overexpression also led to decreased cell migration, invasion and proliferation (to a more modest extent) while loss of MAL2 expression reversed the phenotypes. Mutational analysis revealed that a putative Ena/VASP homology 1 recognition site confers the MAL2-phenotype suggesting its role in tumor suppression involves actin remodeling. To reconcile decreased MAL2 protein expression in human carcinomas and its anti-oncogenic phenotypes with increased transcript levels, we propose a transcriptional regulatory model for MAL2 transient overexpression.

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γ-GLUTAMYL CYCLOTRANSFERASE: A NEW GENETIC POLYMORPHISM IN THE MOUSE (MUS MUSCULUS) LINKED TO LYT—2

Genetics ◽

10.1093/genetics/99.1.109 ◽

1981 ◽

Vol 99 (1) ◽

pp. 109-116

Author(s):

Natalie Tulchin ◽

Benjamin A Taylor

Keyword(s):

Congenic Strain ◽

Inbred Mouse ◽

Inbred Strains ◽

F1 Hybrids ◽

Mouse Strains ◽

Chromosome 6 ◽

Dominant Inheritance ◽

Major Band ◽

A Minor ◽

Map Distance

ABSTRACT Electrophoretically variant forms of γ-glutamyl cyclotransferase have been identified in red cells of inbred mouse strains. Each inbred strain exhibited a major band of activity and a minor band that migrated more anodally. The polymorphism affects the migration of both the major and minor bands in a similar way. F1 hybrids between strains with fast forms (A/J) and strains with the slow forms (C57BL/6J) exhibited a four-banded pattern consistent with co-dominant inheritance. The patterns observed in backcross and F2 mice were consistent with the segregation of a pair of autosomal co-dominant alleles. Recombinant inbred strains and a congenic strain were used to show that the locus controlling γ-glutamyl cyclotransferase (Ggc) is linked to Lyt-2, a lymphocyte alloantigen locus on chromosome 6, with an estimated map distance of 5.0 ± 2.5 centimorgans.

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Investigation of SPARC protein expression levels at dopaminergic system in mouse brain treated with repeated morphine administration

Neuroscience Research ◽

10.1016/s0168-0102(00)81595-3 ◽

2000 ◽

Vol 38 ◽

pp. S125

Author(s):

S Akiduki

Keyword(s):

Protein Expression ◽

Mouse Brain ◽

Dopaminergic System ◽

Expression Levels ◽

Morphine Administration

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A cell type‐specific expression map of NCoR1 and SMRT transcriptional co‐repressors in the mouse brain

The Journal of Comparative Neurology ◽

10.1002/cne.24886 ◽

2020 ◽

Vol 528 (13) ◽

pp. 2218-2238 ◽

Cited By ~ 2

Author(s):

Attilio Iemolo ◽

Patricia Montilla‐Perez ◽

I‐Chi Lai ◽

Yinuo Meng ◽

Syreeta Nolan ◽

...

Keyword(s):

Mouse Brain ◽

Cell Type ◽

Specific Expression ◽

Cell Type Specific Expression ◽

A Cell ◽

Cell Type Specific

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Genetic Control of Mammalian Meiotic Recombination. I. Variation in Exchange Frequencies Among Males From Inbred Mouse Strains

Genetics ◽

10.1093/genetics/162.1.297 ◽

2002 ◽

Vol 162 (1) ◽

pp. 297-306 ◽

Cited By ~ 13

Author(s):

Kara E Koehler ◽

Jonathan P Cherry ◽

Audrey Lynn ◽

Patricia A Hunt ◽

Terry J Hassold

Keyword(s):

Meiotic Recombination ◽

Inbred Mouse ◽

Inbred Strains ◽

Male Meiosis ◽

Mouse Strains ◽

Recombination Rates ◽

The Mean ◽

Genetic Background Effects ◽

Exchange Patterns ◽

Positive Interference

AbstractGenetic background effects on the frequency of meiotic recombination have long been suspected in mice but never demonstrated in a systematic manner, especially in inbred strains. We used a recently described immunostaining technique to assess meiotic exchange patterns in male mice. We found that among four different inbred strains—CAST/Ei, A/J, C57BL/6, and SPRET/Ei—the mean number of meiotic exchanges per cell and, thus, the recombination rates in these genetic backgrounds were significantly different. These frequencies ranged from a low of 21.5 exchanges in CAST/Ei to a high of 24.9 in SPRET/Ei. We also found that, as expected, these crossover events were nonrandomly distributed and displayed positive interference. However, we found no evidence for significant differences in the patterns of crossover positioning between strains with different exchange frequencies. From our observations of >10,000 autosomal synaptonemal complexes, we conclude that achiasmate bivalents arise in the male mouse at a frequency of 0.1%. Thus, special mechanisms that segregate achiasmate chromosomes are unlikely to be an important component of mammalian male meiosis.

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EVIDENCE THAT TWO LOCI PREDOMINANTLY DETERMINE THE DIFFERENCE IN SUSCEPTIBILITY TO THE HIGH PRESSURE NEUROLOGIC SYNDROME TYPE I SEIZURE IN MICE

Genetics ◽

10.1093/genetics/99.2.285 ◽

1981 ◽

Vol 99 (2) ◽

pp. 285-307

Author(s):

R D McCall ◽

D Frierson

Keyword(s):

High Pressure ◽

Inbred Mouse ◽

Inbred Strains ◽

Chromosome 17 ◽

Seizure Threshold ◽

Mouse Strains ◽

Compression Rate ◽

Type I ◽

Major Locus ◽

The Difference

ABSTRACT Most mammals tested, when exposed to increasing pressure in helium/oxygen atmospheres, exhibit progressive motor disturbances culminating in two, usually successive, well-differentiated convulsive seizures. The seizures are highly reproducible components of the constellation of events that collectively constitute the High Pressure Neurologic Syndrome (HPNS). In the present study, we present evidence that the mean difference in seizure threshold pressures of the first seizure to occur (HPNS Type I) between inbred mouse strains DBA/2J and C57BL/6J is predominantly determined (> 60%) by the expression of a major locus—possibly linked to the H-2 locus on chromosome 17—and a minor locus, probably unlinked. This outcome is derived from applications of the maximum likelihood modeling procedure of Elston and Stewart (1973) and Stewart and Elston (1973) to eleven models of genetic determinacy and tests (including breeding tests) of "preferred" models so derived using BXD recombinant inbred strains that show the following: The major locus exhibits conditional dominance characteristics depending upon compression rate and minor locus genotype. At a constant mean compression rate of 100 atm hr-1, the major locus manifests strong, though incomplete, dominance apparently independent of minor locus genotype. Its expression is, however, highly sensitive to compression rate, losing its dominance altogether at a linear rate of 1,000 atm hr-1. The major locus interacts with the weakly dominant and relatively compression-rate-insensitive minor locus to retain dominance at fast compression only when the dominant alleles of both loci are present. A principal finding of this study is that employing two compression rates permits fuller genetic characterization of murine high-pressure seizure susceptibility differences than could be achieved by use of a single compression rate.

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Discovery and refinement of muscle weight QTLs in B6 × D2 advanced intercross mice

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2014 ◽

2014 ◽

Vol 46 (16) ◽

pp. 571-582 ◽

Cited By ~ 9

Author(s):

P. Carbonetto ◽

R. Cheng ◽

J. P. Gyekis ◽

C. C. Parker ◽

D. A. Blizard ◽

...

Keyword(s):

Inbred Strains ◽

Mouse Strains ◽

Missense Mutations ◽

Muscle Weight ◽

Hindlimb Muscles ◽

Hindlimb Muscle ◽

Causal Genes ◽

Snp Panel ◽

Genomic Regions ◽

Genetic Contributions

The genes underlying variation in skeletal muscle mass are poorly understood. Although many quantitative trait loci (QTLs) have been mapped in crosses of mouse strains, the limited resolution inherent in these conventional studies has made it difficult to reliably pinpoint the causal genetic variants. The accumulated recombination events in an advanced intercross line (AIL), in which mice from two inbred strains are mated at random for several generations, can improve mapping resolution. We demonstrate these advancements in mapping QTLs for hindlimb muscle weights in an AIL ( n = 832) of the C57BL/6J (B6) and DBA/2J (D2) strains, generations F8–F13. We mapped muscle weight QTLs using the high-density MegaMUGA SNP panel. The QTLs highlight the shared genetic architecture of four hindlimb muscles and suggest that the genetic contributions to muscle variation are substantially different in males and females, at least in the B6D2 lineage. Out of the 15 muscle weight QTLs identified in the AIL, nine overlapped the genomic regions discovered in an earlier B6D2 F2 intercross. Mapping resolution, however, was substantially improved in our study to a median QTL interval of 12.5 Mb. Subsequent sequence analysis of the QTL regions revealed 20 genes with nonsense or potentially damaging missense mutations. Further refinement of the muscle weight QTLs using additional functional information, such as gene expression differences between alleles, will be important for discerning the causal genes.

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